6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors

ABSTRACT

The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2.

RELATED APPLICATIONS

This application claims priority to and benefit of U.S. Application No.63/020,645, filed May 6, 2020, U.S. Application No. 63/087,717, filedOct. 5, 2020, and U.S. Application No. 63/130,254, filed Dec. 23, 2020,the entire contents of each of which are hereby incorporated byreference in their entirety.

BACKGROUND

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase involved in theJAK-STAT signaling pathway, which plays a role in cell processes such asimmunity, cell division, and cell death. Dysfunction of the JAK-STATpathway is implicated in various diseases, including cancer and otherproliferative diseases, as well as diseases of the immune system. Forexample, essentially all BCR-ABL1-negative myeloproliferative neoplasmsare associated with mutations that activate JAK2. In particular,JAK2V617F is the most prevalent mutation in myeloproliferativeneoplasms, occurring in approx. 70% of all patients, and in up to 95% ofpatients with polycythemia vera. (Vainchenker, W., Kralovics, R. Blood2017, 129(6):667-79). Even less common mutations, such as in MPL andCALR, have been shown to effect activation of JAK2, thereby initiatingand/or driving disease progression. (Vainchenker, W. et al.,F1000Research 2018, 7(F1000 Faculty Rev):82). Furthermore, polymorphismsin JAK2 have been linked to various autoimmune diseases and inflammatoryconditions, such as psoriasis and inflammatory bowel disease. (O'Shea,J. J. et al., Ann. Rheum. Dis. 2013 April, 72:ii111-ii115). Increasedsignaling through JAK2, as well as other members of the JAK family, isalso associated with atopic dermatitis. (Rodrigues, M. A. and Torres, T.J. Derm. Treat. 2019, 31(1):33-40).

Inhibitors of JAKs (e.g., JAK2) are classified based on their bindingmode. All currently approved JAK inhibitors are Type I inhibitors, whichare those that bind the ATP-binding site in the active conformation ofthe kinase domain, thereby blocking catalysis (Vainchenker, W. et al.).However, increased phosphorylation of the JAK2 activation loop isobserved with Type I inhibitors and may lead to acquired resistance incertain patients (Meyer S. C., Levine, R. L. Clin. Cancer Res. 2014,20(8):2051-9). Type II inhibitors, on the other hand, bind theATP-binding site of the kinase domain in the inactive conformation and,therefore, may avoid hyperphosphorylation observed with Type Iinhibitors (Wu, S. C. et al. Cancer Cell 2015 Jul. 13, 28(1):29-41).

SUMMARY

The present disclosure provides compounds useful for inhibiting JAK2. Insome embodiments, provided compounds are useful for, among other things,treating and/or preventing diseases, disorders, or conditions associatedwith JAK2.

In some embodiments, the present disclosure provides a compound ofFormula I-1:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, W, X,Y, Z, R¹, R², and R^(a) are as defined herein.

In some embodiments, the present disclosure provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, X, Y,Z, R¹, R², and R^(a) are as defined herein.

DETAILED DESCRIPTION Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

Unless otherwise stated, structures depicted herein are meant to includeall stereoisomeric (e.g., enantiomeric or diastereomeric) forms of thestructure, as well as all geometric or conformational isomeric forms ofthe structure. For example, the R and S configurations of eachstereocenter are contemplated as part of the disclosure. Therefore,single stereochemical isomers, as well as enantiomeric, diastereomic,and geometric (or conformational) mixtures of provided compounds arewithin the scope of the disclosure. For example, in some case, Table 1shows one or more stereoisomers of a compound, and unless otherwiseindicated, represents each stereoisomer alone and/or as a mixture.Unless otherwise stated, all tautomeric forms of provided compounds arewithin the scope of the disclosure.

Unless otherwise indicated, structures depicted herein are meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures including replacement of hydrogen by deuterium or tritium, orreplacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within thescope of this disclosure.

Aliphatic: The term “aliphatic” refers to a straight-chain (i.e.,unbranched) or branched, optionally substituted hydrocarbon chain thatis completely saturated or that contains one or more units ofunsaturation, or a monocyclic or bicyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation but whichis not aromatic (also referred to herein as “carbocyclic” or“cycloaliphatic”), that has a single point of attachment to the rest ofthe molecule. Unless otherwise specified, aliphatic groups contain 1-12aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-6 aliphatic carbon atoms (e.g., C₁₋₆). In some embodiments, aliphaticgroups contain 1-5 aliphatic carbon atoms (e.g., C₁₋₅). In otherembodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g.,C₁₋₄). In still other embodiments, aliphatic groups contain 1-3aliphatic carbon atoms (e.g., C₁₋₃), and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C₁₋₂).Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof. In some embodiments, “aliphatic” refers to astraight-chain (i.e., unbranched) or branched, optionally substitutedhydrocarbon chain that is completely saturated or that contains one ormore units of unsaturation that has a single point of attachment to therest of the molecule.

Alkyl: The term “alkyl”, used alone or as part of a larger moiety,refers to a saturated, optionally substituted straight or branchedhydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8,1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C₁₋₁₂, C₁₋₁₀, C₁₋₈, C₁₋₆,C₁₋₄, C₁₋₃, or C₁₋₂). Exemplary alkyl groups include methyl, ethyl,propyl, butyl, pentyl, hexyl, and heptyl.

Carbocyclyl: The terms “carbocyclyl,” “carbocycle,” and “carbocyclicring” as used herein, refer to saturated or partially unsaturated cyclicaliphatic monocyclic, bicyclic, or polycyclic ring systems, as describedherein, having from 3 to 14 members, wherein the aliphatic ring systemis optionally substituted as described herein. Carbocyclic groupsinclude, without limitation, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. Insome embodiments, “carbocyclyl” (or “cycloaliphatic”) refers to anoptionally substituted monocyclic C₃-C₈ hydrocarbon, or an optionallysubstituted C₇-C₁₀ bicyclic hydrocarbon that is completely saturated orthat contains one or more units of unsaturation, but which is notaromatic, that has a single point of attachment to the rest of themolecule. The term “cycloalkyl” refers to an optionally substitutedsaturated ring system of about 3 to about 10 ring carbon atoms. In someembodiments, cycloalkyl groups have 3-6 carbons. Exemplary monocycliccycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl. The term “cycloalkenyl” refers to anoptionally substituted non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and havingabout 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenylrings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety,refers to an optionally substituted straight or branched hydrocarbonchain having at least one double bond and having (unless otherwisespecified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C₂₋₁₂,C₂₋₁₀, C₂₋₈, C₂₋₆, C₂₋₄, or C₂₋₃). Exemplary alkenyl groups includeethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety,refers to an optionally substituted straight or branched chainhydrocarbon group having at least one triple bond and having (unlessotherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C₂₋₁₂, C₂₋₁₀, C₂₋₈, C₂₋₆, C₂₋₄, or C₂₋₃). Exemplary alkynylgroups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, andheptynyl.

Aryl: The term “aryl” refers to monocyclic and bicyclic ring systemshaving a total of six to fourteen ring members (e.g., C₆₋₁₄), wherein atleast one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In some embodiments, “aryl”refers to an aromatic ring system which includes, but not limited to,phenyl, naphthyl, anthracyl and the like, which may bear one or moresubstituents. Unless otherwise specified, “aryl” groups arehydrocarbons.

Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or aspart of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”,refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms(e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-memberedbicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclicarray; and having, in addition to carbon atoms, from one to fiveheteroatoms. Exemplary heteroaryl groups include, without limitation,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl,indolizinyl, purinyl, naphthyridinyl, pteridinyl,imidazo[1,2a]-imidazo[1,2-a]pyridinyl, thienopyrimidinyl,triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3heteroatoms). Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl,pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzoisoxazolyl. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring”, “heteroaryl group”, or “heteroaromatic”, any of which termsinclude rings that are optionally substituted.

Heteroatom: The term “heteroatom” as used herein refers to nitrogen,oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur,and any quaternized form of a basic nitrogen.

Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”,and “heterocyclic ring” are used interchangeably and refer to a stable3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclicmoiety that is either saturated or partially unsaturated, and having, inaddition to carbon atoms, one or more, such as one to four, heteroatoms,as defined above. When used in reference to a ring atom of aheterocycle, the term “nitrogen” includes a substituted nitrogen. As anexample, in a saturated or partially unsaturated ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen maybe N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR⁺(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attachedto its pendant group at any heteroatom or carbon atom that results in astable structure and any of the ring atoms can be optionallysubstituted. Examples of such saturated or partially unsaturatedheterocyclic radicals include, without limitation, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl,piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-,bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. A bicyclic heterocyclic ring also includesgroups in which the heterocyclic ring is fused to one or more aryl,heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclicgroups include indolinyl, isoindolinyl, benzodioxolyl,1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, andtetrahydroquinolinyl. A bicyclic heterocyclic ring can also be aspirocyclic ring system (e.g., 7- to 11-membered spirocyclic fusedheterocyclic ring having, in addition to carbon atoms, one or moreheteroatoms as defined above (e.g., one, two, three or fourheteroatoms)).

Partially Unsaturated: As used herein, the term “partially unsaturated”,when referring to a ring moiety, means a ring moiety that includes atleast one double or triple bond between ring atoms. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic (e.g., aryl orheteroaryl) moieties, as herein defined.

Patient or subject: As used herein, the term “patient” or “subject”refers to any organism to which a provided composition is or may beadministered, e.g., for experimental, diagnostic, prophylactic,cosmetic, and/or therapeutic purposes. Typical patients or subjectsinclude animals (e.g., mammals such as mice, rats, rabbits, non-humanprimates, and/or humans). In some embodiments, a patient is a human. Insome embodiments, a patient or a subject is suffering from orsusceptible to one or more disorders or conditions. In some embodiments,a patient or subject displays one or more symptoms of a disorder orcondition. In some embodiments, a patient or subject has been diagnosedwith one or more disorders or conditions. In some embodiments, a patientor a subject is receiving or has received certain therapy to diagnoseand/or to treat a disease, disorder, or condition.

Substituted or optionally substituted: As described herein, compounds ofthis disclosure may contain “optionally substituted” moieties. Ingeneral, the term “substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designatedmoiety are replaced with a suitable substituent. “Substituted” appliesto one or more hydrogens that are either explicit or implicit from thestructure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group may have asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposes providedherein. Groups described as being “substituted” preferably have between1 and 4 substituents, more preferably 1 or 2 substituents. Groupsdescribed as being “optionally substituted” may be unsubstituted or be“substituted” as described above.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR^(o) ₂;—C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o), —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; —SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁ Ph, —CH₂-(5- to 6-membered heteroaryl ring), or a 3- to6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a 3- to12-membered saturated, partially unsaturated, or aryl mono- or bicyclicring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂, —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 3- to 6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O (“oxo”), ═S,═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*,—O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independent occurrenceof R* is selected from hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, or an unsubstituted 3- to 6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Suitable divalentsubstituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: —O(CR*₂)₂₋₃O—, wherein eachindependent occurrence of R* is selected from hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 3- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, or an unsubstituted 3- to 6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or, notwithstanding thedefinition above, two independent occurrences of R^(†), taken togetherwith their intervening atom(s) form an unsubstituted 3- to 12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 3- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Treat: As used herein, the term “treat” (also “treatment” or “treating”)refers to any administration of a therapy that partially or completelyalleviates, ameliorates, relives, inhibits, delays onset of, reducesseverity of, and/or reduces incidence of one or more symptoms, features,and/or causes of a particular disease, disorder, and/or condition. Insome embodiments, such treatment may be of a subject who does notexhibit signs of the relevant disease, disorder and/or condition and/orof a subject who exhibits only early signs of the disease, disorder,and/or condition. Alternatively or additionally, such treatment may beof a subject who exhibits one or more established signs of the relevantdisease, disorder and/or condition. In some embodiments, treatment maybe of a subject who has been diagnosed as suffering from the relevantdisease, disorder, and/or condition.

Provided Compounds

The present disclosure provides a compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x) and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   each R³ is independently hydrogen or optionally substituted C₁₋₆    aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form an optionally substituted 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 0-2 additional heteroatoms independently    selected from nitrogen, oxygen, and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.

In some embodiments, the present disclosure provides a compound ofFormula I-1, or a pharmaceutically acceptable salt thereof, wherein:

-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x) and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   each R³ is independently hydrogen or optionally substituted C₁₋₆    aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form a 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 0-2    additional heteroatoms independently selected from nitrogen, oxygen,    and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.

In some embodiments, the present disclosure provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(x) and R^(y) are each independently hydrogen, optionally    substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form a 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 0-2    additional heteroatoms independently selected from nitrogen, oxygen,    and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.

In some embodiments, the present disclosure provides a compound ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), R^(x), and R^(y) are as defined above for Formula I-1 anddescribed in classes and subclasses herein, both singly and incombination. In some embodiments, Ring A, L, Z, R¹, R², R^(a), and R^(y)are as defined above for Formula I.

In some embodiments, the present disclosure provides a compound ofFormula III:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), R^(x), and R^(y) are as defined above for Formula I-1 anddescribed in classes and subclasses herein, both singly and incombination. In some embodiments, Ring A, L, Z, R¹, R², R^(a), R^(x),and R^(y) are as defined above for Formula I.

In some embodiments, the present disclosure provides a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), and R^(x) are as defined above for Formula I-1 and describedin classes and subclasses herein, both singly and in combination. Insome embodiments, Ring A, L, Z, R¹, R², R^(a), and R^(x) are as definedabove for Formula I.

In some embodiments, the present disclosure provides a compound ofFormula I′:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), X, and Y are as defined above for Formula I-1 and describedin classes and subclasses herein, both singly and in combination; and

-   R^(b) is hydrogen, halogen, —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,    —C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,    —OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′, —SO₂N(R)₂, —SO₃R′,    optionally substituted C₁₋₆ aliphatic, optionally substituted 3- to    6-membered saturated or partially unsaturated carbocyclyl,    optionally substituted 3- to 6-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 5- to 6-membered monocyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.

In some embodiments of Formula I′, Ring A, L, Z, R¹, R², R^(a), X, and Yare as defined above for Formula I, and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula II′:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), R^(x), and R^(y) are as defined above for Formula I-1 andR^(b) is as defined above for Formula I′, and described in classes andsubclasses herein, both singly and in combination. In some embodiments,Ring A, L, Z, R¹, R², R^(a), R^(x), and R^(y) are as defined above forFormula I and R^(b) is as defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula III′:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), R^(x), and R^(y) are as defined above for Formula I-1 andR^(b) is as defined above for Formula I′, and described in classes andsubclasses herein, both singly and in combination. In some embodiments,Ring A, L, Z, R¹, R², R^(a), R^(x), and R^(y) are as defined above forFormula I and R^(b) is as defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula IV′:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, Z, R¹,R², R^(a), and R^(x) are as defined above for Formula I-1 and R^(b) isas defined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, Ring A, L,Z, R¹, R², R^(a), and R^(x) are as defined above for Formula I and R^(b)is as defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula I-A:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, X, Y,R′, and R^(a) are as defined above for Formula I-1 and described inclasses and subclasses herein, both singly and in combination. In someembodiments, Ring A, L, X, Y, R′, and R^(a) are as defined above forFormula I.

In some embodiments, the present disclosure provides a compound ofFormula II-A:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, R′,R^(x), R^(y), and R^(a) are as defined above for Formula I-1 anddescribed in classes and subclasses herein, both singly and incombination. In some embodiments, Ring A, L, R′, R^(x), R^(y), and R^(a)are as defined above for Formula I.

In some embodiments, the present disclosure provides a compound ofFormula III-A:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, R′,R^(y), and R^(a) are as defined above for Formula I-1 and described inclasses and subclasses herein, both singly and in combination. In someembodiments, Ring A, L, R′, R^(y), and R^(a) are as defined above forFormula I.

In some embodiments, the present disclosure provides a compound ofFormula IV-A:

or a pharmaceutically acceptable salt thereof, wherein Ring A, L, R′,R^(x), and R^(a) are as defined above for Formula I-1 and described inclasses and subclasses herein, both singly and in combination. In someembodiments, Ring A, L, R′, R^(x), and R^(a) are as defined above forFormula I.

In some embodiments, the present disclosure provides a compound ofFormula I-B:

or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R¹,R², and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, X, Y, Z,R¹, R², and R^(a) are as defined above for Formula I and R^(b) is asdefined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula II-B:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R¹, R²,R^(x), and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, Z, R¹,R², R^(x), R^(y), and R^(a) are as defined above for Formula I and R^(b)is as defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula III-B:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R¹, R²,R^(y), and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, Z, R¹,R², R^(y), and R^(a) are as defined above for Formula I and R^(b) is asdefined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula IV-B:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R¹, R²,R^(x), and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, Z, R¹,R², R^(x), and R^(a) are as defined above for Formula I and R^(b) is asdefined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula I-C:

or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R′, andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, X, Y, R′, and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula II-C:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(x),R^(y), and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, R′,R^(x), R^(y), and R^(a) are as defined above for Formula I and R^(b) isas defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula III-C:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(y), andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, R′, R^(y), and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula IV-C:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(x), andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, R′, R^(x), and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula I-D:

or a pharmaceutically acceptable salt thereof, wherein L, X, Y, Z, R¹,R², and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, X, Y, Z,R¹, R², and R^(a) are as defined above for Formula I and R^(b) is asdefined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula II-D:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R^(x),R^(y), R¹, R², and R^(a) are as defined above for Formula I-1 and R^(b)is as defined above for Formula I′, and described in classes andsubclasses herein, both singly and in combination. In some embodiments,L, Z, R^(x), R^(y), R¹, R², and R^(a) are as defined above for Formula Iand R^(b) is as defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula III-D:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R^(y), R¹,R², and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, Z,R^(y), R¹, R², and R^(a) are as defined above for Formula I and R^(b) isas defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula IV-D:

or a pharmaceutically acceptable salt thereof, wherein L, Z, R^(x), R¹,R², and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, Z,R^(x), R¹, R², and R^(a) are as defined above for Formula I and R^(b) isas defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula I-E:

or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R′, andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, X, Y, R′, and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula II-E:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(x),R^(y), and R^(a) are as defined above for Formula I-1 and R^(b) is asdefined above for Formula I′, and described in classes and subclassesherein, both singly and in combination. In some embodiments, L, R′,R^(x), R^(y), and R^(a) are as defined above for Formula I and R^(b) isas defined above for Formula I′.

In some embodiments, the present disclosure provides a compound ofFormula III-E:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(y), andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, R′, R^(y), and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments, the present disclosure provides a compound ofFormula IV-E:

or a pharmaceutically acceptable salt thereof, wherein L, R′, R^(x), andR^(a) are as defined above for Formula I-1 and R^(b) is as defined abovefor Formula I′, and described in classes and subclasses herein, bothsingly and in combination. In some embodiments, L, R′, R^(x), and R^(a)are as defined above for Formula I and R^(b) is as defined above forFormula I′.

In some embodiments of Formulae I-1, W is CR^(w). In some embodiments, Wis N.

In some embodiments of any of Formulae I-1, I, I′, I-A, I-B, I-C, I-D,and I-E, X is CR^(x). In some embodiments, X is N.

In some embodiments of any of Formulae I-1, I, I′, I-A, I-B, I-C, I-D,and I-E, Y is CR^(y). In some embodiments, Y is N.

In some embodiments of Formulae I-1, W is CR^(w) or N, X is CR^(x) or N,and Y is CR^(y) or N, and no more than one of W, X, and Y is N. In someembodiments of Formulae I-1, W is CR^(w) or N, X is CR^(x) or N, and Yis CR^(y) or N, and no more than two of W, X, and Y is N.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-B, II-B, III-B, IB-B, I-D, II-D, III-D, and IV-D, Z is —O—.In some embodiments, Z is —NR^(z)—. In some embodiments Z is —NH—.

In some embodiments of any of Formulae I-1, R^(w) is hydrogen, halogen,optionally substituted C₁₋₆ aliphatic, or —CN. In some embodiments,R^(w) is hydrogen, optionally substituted C₁₋₆ aliphatic, or —CN. Insome embodiments, R^(w) is hydrogen or methyl. In some embodiments,R^(w) is hydrogen, methyl, or —CN. In some embodiments, R^(w) ishydrogen. In some embodiments, R^(w) is halogen. In some embodiments,R^(w) is fluoro. In some embodiments, R^(w) is chloro. In someembodiments, R^(w) is bromo. In some embodiments, R^(w) is iodo. In someembodiments, R^(w) is —OR³. In some embodiments, R^(w) is —OR³, whereinR³ is optionally substituted C₁₋₆ aliphatic. In some embodiments, Y isN, W is CR^(w), and R^(w) is —OR³ wherein R³ is optionally substitutedC₁₋₆ aliphatic. In some embodiments, R^(w) is —N(R³)₂. In someembodiments, R^(w) is —SR³. In some embodiments, R^(w) is —SR³, whereinR³ is optionally substituted C₁₋₆ aliphatic. In some embodiments, Y isN, W is CR^(w), and R^(w) is —SR³ wherein R³ is optionally substitutedC₁₋₆ aliphatic. In some embodiments, R^(w) is optionally substitutedC₁₋₆ aliphatic. In some embodiments, R^(w) is optionally substitutedstraight-chain or branched C₁₋₆ aliphatic (i.e., optionally substitutedacyclic C₁₋₆ aliphatic). In some embodiments, R^(w) is optionallysubstituted C₁₋₆ alkyl. In some embodiments, R^(w) is optionallysubstituted C₁₋₄ alkyl. In some embodiments, R^(w) is unsubstituted C₁₋₄alkyl. In some embodiments, R^(w) is optionally substituted C₁₋₂ alkyl.In some embodiments, R^(w) is optionally substituted methyl (e.g.,methyl optionally substituted with one or more fluoro). In someembodiments, R^(w) is methyl. In some embodiments, R^(w) is —CN.

In some embodiments of any of Formulae I-1, I, II, IV, I′, II′, IV′,I-A, II-A, IV-A, I-B, II-B, IV-B, I-C, II-C, IV-C, I-D, II-D, IV-D, I-E,II-E, and IV-E, R^(x) is hydrogen, halogen, optionally substituted C₁₋₆aliphatic, or —CN. In some embodiments, R^(x) is hydrogen, halogen,—OR³, optionally substituted C₁₋₆ aliphatic, or —CN. In someembodiments, R^(x) is hydrogen, optionally substituted C₁₋₆ aliphatic,or —CN. In some embodiments, R^(x) is halogen, —OR³, —N(R³)₂, —SR³, or—CN. In some embodiments, R^(x) is halogen, —OR³, or —CN. In someembodiments, R^(x) is hydrogen or methyl. In some embodiments, R^(x) ishydrogen, methyl, or —CN. In some embodiments, R^(x) is hydrogen. Insome embodiments, R^(x) is halogen. In some embodiments, R^(x) isfluoro. In some embodiments, R^(x) is chloro. In some embodiments, R^(x)is bromo. In some embodiments, R^(x) is iodo. In some embodiments, R^(x)is —OR³. In some embodiments, R^(x) is —OCH₃. In some embodiments, R^(x)is —N(R³)₂. In some embodiments, R^(x) is —SR³. In some embodiments,R^(x) is optionally substituted C₁₋₆ aliphatic. In some embodiments,R^(x) is optionally substituted straight-chain or branched C₁₋₆aliphatic (i.e., optionally substituted acyclic C₁₋₆ aliphatic). In someembodiments, R^(x) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(x) is optionally substituted C₁₋₄ alkyl. In someembodiments, R^(x) is unsubstituted C₁₋₄ alkyl. In some embodiments,R^(x) is optionally substituted C₁₋₂ alkyl. In some embodiments, R^(x)is ethyl. In some embodiments, R^(x) is optionally substituted methyl(e.g., methyl optionally substituted with one or more fluoro, e.g.,—CHF₂). In some embodiments, R^(x) is methyl. In some embodiments, R^(x)is —CN.

In some embodiments of any of Formulae I-1, I, II, III, I′, II′, III′,I-A, II-A, III-A, I-B, II-B, III-B, I-C, II-C, III-C, I-D, II-D, III-D,I-E, II-E, and III-E, R^(y) is hydrogen, halogen, optionally substitutedC₁₋₆ aliphatic, or —CN. In some embodiments, R^(y) is hydrogen,optionally substituted C₁₋₆ aliphatic, or —CN. In some embodiments,R^(y) is hydrogen or methyl. In some embodiments, R^(y) is hydrogen,methyl, or —CN. In some embodiments, R^(y) is hydrogen. In someembodiments, R^(y) is halogen. In some embodiments, R^(y) is fluoro. Insome embodiments, R^(y) is chloro. In some embodiments, R^(y) is bromo.In some embodiments, R^(y) is iodo. In some embodiments, R^(y) is —OR³.In some embodiments, R^(y) is —OR³, wherein R³ is optionally substitutedC₁₋₆ aliphatic. In some embodiments, W is N, Y is CR^(y), and R^(y) is—OR³ wherein R³ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R^(y) is —N(R³)₂. In some embodiments, R^(y) is —SR³. Insome embodiments, R^(y) is —SR³, wherein R³ is optionally substitutedC₁₋₆ aliphatic. In some embodiments, W is N, Y is CR^(y), and R^(y) is—SR³ wherein R³ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R^(y) is optionally substituted C₁₋₆ aliphatic. In someembodiments, R^(y) is optionally substituted straight-chain or branchedC₁₋₆ aliphatic (i.e., optionally substituted acyclic C₁₋₆ aliphatic). Insome embodiments, R^(y) is optionally substituted C₁₋₆ alkyl. In someembodiments, R^(y) is optionally substituted C₁₋₄ alkyl. In someembodiments, R^(y) is unsubstituted C₁₋₄ alkyl. In some embodiments,R^(y) is optionally substituted C₁₋₂ alkyl. In some embodiments, R^(y)is optionally substituted methyl (e.g., methyl optionally substitutedwith one or more fluoro). In some embodiments, R^(y) is methyl. In someembodiments, R^(y) is —CN.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-B, II-B, III-B, IV-B, I-D, II-D, III-D, IV-D, I-E, II-E,III-E, and IV-E, R^(z) is hydrogen. In some embodiments, R^(z) isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R^(z) isoptionally substituted straight-chain or branched C₁₋₆ aliphatic (i.e.,optionally substituted acyclic C₁₋₆ aliphatic). In some embodiments,R^(z) is optionally substituted C₁₋₆ alkyl. In some embodiments, R^(z)is optionally substituted C₁₋₄ alkyl. In some embodiments, R^(z) isunsubstituted C₁₋₄ alkyl. In some embodiments, R^(z) is optionallysubstituted C₁₋₂ alkyl. In some embodiments, R^(z) is unsubstituted C₁₋₂alkyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-B, II-B, III-B, IV-B, I-D, II-D, III-D, and IV-D, R¹ is—N(R)C(O)R′ or —C(O)N(R)₂. In some embodiments, R¹ is —N(R)C(O)R′,—C(O)N(R)₂, or —N(R)C(O)N(R)₂. In some embodiments, R¹ is —N(R)C(O)R′.In some embodiments, R¹ is —N(H)C(O)R′. In some embodiments, R¹ is—N(R)C(O)(optionally substituted C₁₋₆ aliphatic). In some embodiments,R¹ is —N(H)C(O)(optionally substituted C₁₋₆ aliphatic). In someembodiments, R¹ is —N(R)C(O)R′, wherein R′ is C₁₋₆ aliphatic optionallysubstituted with —OC₁₋₆ alkyl or a 3- to 7-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R¹ is —N(H)C(O)R′,wherein R′ is C₁₋₆ aliphatic optionally substituted with —OC₁₋₆ alkyl ora 3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R¹ is —N(R)C(O)(C₁₋₆ aliphatic). In some embodiments,R¹ is —N(H)C(O)(C₁₋₆ aliphatic). In some embodiments, R¹ is—N(R)C(O)(straight-chain or branched C₁₋₆ aliphatic). In someembodiments, R¹ is —N(H)C(O)(straight-chain or branched C₁₋₆ aliphatic).In some embodiments, R¹ is —N(R)C(O)(optionally substituted C₁₋₆ alkyl).In some embodiments, R¹ is —N(H)C(O)(optionally substituted C₁₋₆ alkyl).In some embodiments, R¹ is —N(R)C(O)R′, wherein R′ is C₁₋₆ alkyloptionally substituted with —OC₁₋₆ alkyl or a 3- to 7-membered saturatedmonocyclic heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, R¹ is—N(H)C(O)R′, wherein R′ is C₁₋₆ alkyl optionally substituted with —OC₁₋₆alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R¹ is —N(R)C(O)(C₁₋₆ alkyl). In some embodiments, R¹is —N(H)C(O)(C₁₋₆ alkyl). In some embodiments, R¹ is—N(R)C(O)(optionally substituted C₁₋₄ alkyl). In some embodiments, R¹ is—N(H)C(O)(optionally substituted C₁₋₄ alkyl). In some embodiments, R¹ is—N(R)C(O)R′, wherein R′ is C₁₋₄ alkyl optionally substituted with —OC₁₋₆alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R¹ is —N(H)C(O)R′, wherein R′ is C₁₋₄ alkyl optionallysubstituted with —OC₁₋₆ alkyl or a 3- to 7-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R¹ is —N(R)C(O)(C₁₋₄alkyl). In some embodiments, R¹ is —N(H)C(O)(C₁₋₄ alkyl). In someembodiments, R¹ is —N(R)C(O)(optionally substituted C₁₋₂ alkyl). In someembodiments, R¹ is —N(H)C(O)(optionally substituted C₁₋₂ alkyl). In someembodiments, R¹ is —N(R)C(O)R′, wherein R′ is C₁₋₂ alkyl optionallysubstituted with —OC₁₋₆ alkyl or a 3- to 7-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R¹ is —N(H)C(O)R′,wherein R′ is C₁₋₂ alkyl optionally substituted with —OC₁₋₆ alkyl or a3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R¹ is —N(R)C(O)(C₁₋₂ alkyl). In some embodiments, R¹is —N(H)C(O)(C₁₋₂ alkyl). In some embodiments, R¹ is —N(R)C(O)CH₃. Insome embodiments, R¹ is —N(H)C(O)CH₃. In some embodiments, R¹ is—N(R)C(O)(optionally substituted C₃₋₇ carbocyclyl). In some embodiments,R¹ is —N(H)C(O)(optionally substituted C₃₋₇ carbocyclyl). In someembodiments, R¹ is —N(R)C(O)(optionally substituted cyclopropyl). Insome embodiments, R¹ is —N(H)C(O)(optionally substituted cyclopropyl).In some embodiments, R¹ is —N(R)C(O)CH₃ or —N(R)C(O)(cyclopropyl). Insome embodiments, R¹ is R¹ is —N(H)C(O)CH₃ or —N(H)C(O)(cyclopropyl).

In some embodiments, R¹ is —C(O)N(R)₂. In some embodiments, R¹ is—C(O)N(R)(C₁₋₆ aliphatic). In some embodiments, R¹ is —C(O)N(H)(C₁₋₆aliphatic). In some embodiments, R¹ is —C(O)N(R)(straight-chain orbranched C₁₋₆ aliphatic). In some embodiments, R¹ is—C(O)N(H)(straight-chain or branched C₁₋₆ aliphatic). In someembodiments, R¹ is —C(O)N(R)(C₁₋₆ alkyl). In some embodiments, R¹ is—C(O)N(H)(C₁₋₆ alkyl). In some embodiments, R¹ is —C(O)N(R)(C₁₋₄ alkyl).In some embodiments, R¹ is —C(O)N(H)(C₁₋₄ alkyl). In some embodiments,R¹ is —C(O)N(R)(C₁₋₂ alkyl). In some embodiments, R¹ is —C(O)N(H)(C₁₋₂alkyl). In some embodiments, R¹ is —C(O)N(R)CH₃. In some embodiments, R¹is —C(O)N(H)(R).

In some embodiments, R¹ is —N(R)₂. In some embodiments, R¹ is —N(H)(R).

In some embodiments, R¹ is —N(R)C(O)N(R)₂. In some embodiments, R¹ is—N(R)C(O)N(R)₂, wherein the two R groups attached to the same nitrogenare taken together to form an optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 0-2additional heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R¹ is —N(R)C(O)N(R)₂, wherein the two Rgroups attached to the same nitrogen are taken together to form a 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 0-2 additional heteroatoms independently selected from nitrogen,oxygen, and sulfur optionally substituted with one or more halogen, C₁₋₆alkyl, and —O(C₁₋₆ alkyl). In some embodiments, R¹ is —N(R)C(O)N(R)₂,wherein the two R groups attached to the same nitrogen are takentogether to form an optionally substituted 3- to 5-membered saturatedmonocyclic heterocyclyl having 0-1 additional heteroatoms. In someembodiments, R¹ is —N(R)C(O)N(R)₂, wherein the two R groups attached tothe same nitrogen are taken together to form an optionally substituted4-membered saturated monocyclic heterocyclyl having 0-1 additionalheteroatoms. In some embodiments, R¹ is —N(R)C(O)N(R)₂, wherein the twoR groups attached to the same nitrogen are taken together to form a 3-to 5-membered saturated monocyclic heterocyclyl having 0-1 additionalheteroatoms optionally substituted with one or more halogen, C₁₋₆ alkyl,and —O(C₁₋₆ alkyl). In some embodiments, R¹ is —N(R)C(O)N(R)₂, whereinthe two R groups attached to the same nitrogen are taken together toform a 4-membered saturated monocyclic heterocyclyl having 0-1additional heteroatoms optionally substituted with one or more halogen,C₁₋₆ alkyl, and —O(C₁₋₆ alkyl). In some embodiments, R¹ is—N(H)C(O)N(R)₂. In some embodiments, R¹ is —N(H)C(O)N(R)₂, wherein thetwo R groups attached to the same nitrogen are taken together to form anoptionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 0-2 additional heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R¹ is —N(H)C(O)N(R)₂, wherein the two R groups attached tothe same nitrogen are taken together to form a 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 0-2additional heteroatoms independently selected from nitrogen, oxygen, andsulfur optionally substituted with one or more halogen, C₁₋₆ alkyl, and—O(C₁₋₆ alkyl). In some embodiments, R¹ is —N(H)C(O)N(R)₂, wherein thetwo R groups attached to the same nitrogen are taken together to form anoptionally substituted 3- to 5-membered saturated monocyclicheterocyclyl having 0-1 additional heteroatoms. In some embodiments, R¹is —N(H)C(O)N(R)₂, wherein the two R groups attached to the samenitrogen are taken together to form an optionally substituted 4-memberedsaturated monocyclic heterocyclyl having 0-1 additional heteroatoms. Insome embodiments, R¹ is —N(H)C(O)N(R)₂, wherein the two R groupsattached to the same nitrogen are taken together to form a 3- to5-membered saturated monocyclic heterocyclyl having 0-1 additionalheteroatoms optionally substituted with one or more halogen, C₁₋₆ alkyl,and —O(C₁₋₆ alkyl). In some embodiments, R¹ is —N(H)C(O)N(R)₂, whereinthe two R groups attached to the same nitrogen are taken together toform a 4-membered saturated monocyclic heterocyclyl having 0-1additional heteroatoms optionally substituted with one or more halogen,C₁₋₆ alkyl, and —O(C₁₋₆ alkyl). In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is selected from:

In some embodiments, R¹ is —C(O)N(H)CH₃.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-B, II-B, III-B, IV-B, I-D, II-D, III-D, and IV-D, R² isoptionally substituted straight-chain or branched C₁₋₆ aliphatic (i.e.,optionally substituted acyclic C₁₋₆ aliphatic). In some embodiments, R²is optionally substituted C₁₋₆ alkyl. In some embodiments, R² isoptionally substituted C₁₋₄ alkyl. In some embodiments, R² isunsubstituted C₁₋₄ alkyl. In some embodiments, R² is optionallysubstituted C₁₋₂ alkyl. In some embodiments, R² is unsubstituted C₁₋₂alkyl. In some embodiments, R² is methyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E, each R³is independently hydrogen or optionally substituted C₁₋₄ aliphatic. Insome embodiments, each R³ is independently hydrogen or optionallysubstituted C₁₋₂ aliphatic. In some embodiments, each R³ is hydrogen. Insome embodiments, each R³ is independently optionally substituted C₁₋₆aliphatic. In some embodiments, each R³ is independently optionallysubstituted straight-chain or branched C₁₋₆ aliphatic (i.e., optionallysubstituted acyclic C₁₋₆ aliphatic). In some embodiments, each R³ isindependently optionally substituted C₁₋₄ aliphatic. In someembodiments, each R³ is independently optionally substitutedstraight-chain or branched C₁₋₄ aliphatic (i.e., optionally substitutedacyclic C₁₋₄ aliphatic). In some embodiments, each R³ is independentlyoptionally substituted C₁₋₂ aliphatic. In some embodiments, each R³ ismethyl. In some embodiments, each R³ is independently hydrogen or C₁₋₆alkyl. In some embodiments, each R³ is independently hydrogen or C₁₋₄alkyl. In some embodiments, each R³ is independently hydrogen or C₁₋₂alkyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, Ring A is (i) optionallysubstituted on a substitutable carbon atom with one or more groupsindependently selected from oxo, halogen, R^(o), —CN, —OR^(o), —SR^(o),—N(R^(o))₂, —NO₂, —C(O)R^(o), —C(O)OR^(o), —C(O)NR^(o) ₂, —OC(O)R^(o),—OC(O)NR^(o) ₂, —OC(O)OR^(o), —OS(O)₂R^(o), —OS(O)₂NR^(o) ₂,—N(R^(o))C(O)R^(o), —N(R^(o))S(O)₂R^(o), —S(O)₂R^(o), and (ii)optionally substituted on a substitutable nitrogen atom with one or moregroups selected from —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—S(O)₂R^(†), —S(O)₂NR^(†) ₂, and —S(O)₂OR^(o). In some embodiments, RingA is (i) optionally substituted on a substitutable carbon atom with oneor more groups independently selected from oxo, halogen, R^(o), —CN,—OR^(o), —SR^(o), —N(R^(o))₂, —NO₂, —C(O)R^(o), —C(O)OR^(o), —C(O)NR^(o)₂, —OC(O)R^(o), —OC(O)NR^(o) ₂, —OC(O)OR^(o), —OS(O)₂R^(o),—OS(O)₂NR^(o) ₂, —N(R^(o)C)(O)R^(o), —N(R^(o))S(O)₂R^(o), —S(O)₂R^(o),—SO₂NR^(o) ₂, and —S(O)₂OR^(o), and (ii) optionally substituted on asubstitutable nitrogen atom with one or more groups selected from—R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —S(O)₂ ^(†), and—S(O)₂NR^(†) ₂. In some embodiments, Ring A is (i) optionallysubstituted on a substitutable carbon atom with one or more groupsindependently selected from oxo, halogen, and R^(o), and (ii) optionallysubstituted on a substitutable nitrogen atom with one or more groupsselected from —R^(†).

In some embodiments, Ring A is optionally substituted with one or moreR^(b) (i.e., in addition to being substituted with -L-R^(a)), whereinR^(b) is as defined in Formula I′ above and described in classes andsubclasses herein. In some embodiments, Ring A is substituted with zero,one, two, three, four, or five R^(b), as valency allows.

In some embodiments, Ring A is optionally substituted 5- to 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, optionally substituted 8- to 10-memberedbicyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or optionally substituted 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

In some embodiments, Ring A is optionally substituted phenyl. In someembodiments, Ring A is not optionally substituted phenyl.

In some embodiments, Ring A is optionally substituted 5- to 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionallysubstituted 5-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted isoxazolyl or pyrazolyl.In some embodiments, Ring A is optionally substituted isoxazolyl,pyrazolyl, or thiazolyl. In some embodiments, Ring A is optionallysubstituted isoxazolyl, pyrazolyl, imidazolyl, or thiazolyl. In someembodiments, Ring A is optionally substituted 6-membered monocyclicheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, Ring A is optionallysubstituted pyridyl, pyridonyl, or pyridazinonyl.

In some embodiments, Ring A is optionally substituted 8- to 10-memberedbicyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, Ring A is optionallysubstituted 8-membered bicyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 9-membered bicyclicheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, Ring A is optionallysubstituted 10-membered bicyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl. In someembodiments, Ring A is optionally substituted 3-membered saturated orpartially unsaturated monocyclic carbocyclyl. In some embodiments, RingA is optionally substituted 4-membered saturated or partiallyunsaturated monocyclic carbocyclyl. In some embodiments, Ring A isoptionally substituted 5-membered saturated or partially unsaturatedmonocyclic carbocyclyl. In some embodiments, Ring A is optionallysubstituted 6-membered saturated or partially unsaturated monocycliccarbocyclyl. In some embodiments, Ring A is optionally substitutedcyclohexyl. In some embodiments, Ring A is optionally substituted7-membered saturated or partially unsaturated monocyclic carbocyclyl.

In some embodiments, Ring A is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring A is optionally substituted 3-membered saturatedor partially unsaturated monocyclic heterocyclyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 4-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 5-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 6-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is optionally substituted 7- to 10-memberedsaturated or partially unsaturated bicyclic heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring A is optionally substituted 7-membered saturatedor partially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 8-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted 9-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substitutedtetrahydrobenzo[d]thiazolyl, tetrahydropyrazole[1,5-a]pyridyl,isoindolinonyl, indolinonyl, or tetrahydroimidazo[1,2-a]pyridyl. In someembodiments, Ring A is optionally substituted 10-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, Ring A is optionally substituted tetrahydroisoquinolinyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E, L is acovalent bond. In some embodiments, L is a bivalent C₁₋₃ straight orbranched hydrocarbon chain. In some embodiments, L is a bivalent C₁₋₂straight or branched hydrocarbon chain. In some embodiments, L ismethylene (—CH₂—). In some embodiments, L is —CH₂CH₂—. In someembodiments, L is —CH₂CH₂CH₂—. In some embodiments, L is a covalent bondor —CH₂—.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E, R^(a)is halogen, optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted 5- to 6-membered monocyclicheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, optionally substituted 3- to 7-membered saturated orpartially unsaturated monocyclic carbocyclyl, optionally substituted 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or optionally substituted 7- to 10-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(a) is halogen, optionally substituted C₁₋₄alkyl, optionally substituted 5-membered monocyclic heteroaryl having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 3- to 6-membered saturated monocycliccarbocyclyl, optionally substituted 3- to 6-membered saturatedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or optionally substituted 7-memberedsaturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(a) is C₁₋₄ alkyl, 3- to 6-membered saturatedmonocyclic heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or 7- to 8-membered saturated,spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(a) is hydrogen. In some embodiments, R^(a) isnot hydrogen.

In some embodiments, R^(a) is halogen. In some embodiments, R^(a) isfluoro, chloro, bromo, or iodo. In some embodiments, R^(a) is fluoro. Insome embodiments, R^(a) is chloro. In some embodiments, R^(a) is nothalogen. In some embodiments, R^(a) is not fluoro. In some embodiments,R^(a) is not chloro.

In some embodiments, R^(a) is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R^(a) is optionally substituted straight-chain orbranched C₁₋₆ aliphatic (i.e., optionally substituted acyclic C₁₋₆aliphatic). In some embodiments, R^(a) is C₁₋₆ aliphatic optionallysubstituted with one or more oxo, halogen, —CN, or —O(C₁₋₆ alkyl). Insome embodiments, R^(a) is C₁₋₆ aliphatic optionally substituted withone or more oxo, halogen, —CN, —OH, or —O(C₁₋₆ alkyl). In someembodiments, R^(a) is C₁₋₆ aliphatic optionally substituted with one ormore oxo, halogen, —CN, or —OCH₃. In some embodiments, R^(a) is C₁₋₆aliphatic optionally substituted with one or more oxo, halogen, —CN,—OH, or —OCH₃. In some embodiments, R^(a) is optionally substituted C₁₋₆alkyl. In some embodiments, R^(a) is C₁₋₆ alkyl. In some embodiments,R^(a) is C₁₋₆ alkyl optionally substituted with one or more oxo,halogen, —CN, or —OCH₃. In some embodiments, R^(a) is C₁₋₆ alkyloptionally substituted with one or more oxo, halogen, —CN, —OH, or—O(C₁₋₆ alkyl) (e.g., —OCH₃). In some embodiments, R^(a) is optionallysubstituted C₁₋₄ alkyl. In some embodiments, R^(a) is C₁₋₄ alkyl. Insome embodiments, R^(a) is C₁₋₄ alkyl optionally substituted with one ormore oxo, halogen, —CN, or —OCH₃. In some embodiments, R^(a) is C₁₋₄alkyl optionally substituted with one or more oxo, halogen, —CN, —OH, or—O(C₁₋₆ alkyl) (e.g., —OCH₃). In some embodiments, R^(a) is optionallysubstituted C₁ alkyl (e.g., methyl). In some embodiments, R^(a) ismethyl, —CF₃, or —CH₂OCH₃. In some embodiments, R^(a) is methyl, —CF₃,—CH₂OCH₃, or —CH₂CN. In some embodiments, R^(a) is optionallysubstituted C₂ alkyl. In some embodiments, R^(a) is —CH₂CH₂OCH₃,—CH₂CH₂OH, or —C(O)CH₃. In some embodiments, R^(a) is —CH₂CH₂OCH₃,—CH₂CH₂OH, —C(O)CH₃—CH₂CH₂F, —CH₂CHF₂, or —CH₂CH₂CN. In someembodiments, R^(a) is optionally substituted C₃ alkyl. In someembodiments, R^(a) is isopropyl or —C(CH₃)₂CN. In some embodiments,R^(a) is isopropyl, —C(CH₃)₂CN, or —CH₂CH(OH)CH₃. In some embodiments,R^(a) is optionally substituted C₄ alkyl. In some embodiments, R^(a) istert-butyl. In some embodiments, R^(a) is tert-butyl or—CH₂CH(CH₃)CH₂OH. In some embodiments, R^(a) is not —CF₃.

In some embodiments, R^(a) is optionally substituted phenyl.

In some embodiments, R^(a) is optionally substituted 5- to 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(a) is optionallysubstituted 5-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(a) is 5-membered monocyclic heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfuroptionally substituted with one or more C₁₋₆ alkyl (e.g., methyl). Insome embodiments, R^(a) is optionally substituted imidazolyl, pyrazolyl,or oxazolyl. In some embodiments, R^(a) is imidazolyl, pyrazolyl, oroxazolyl optionally substituted with one or more C₁₋₆ alkyl (e.g.,methyl). In some embodiments, R^(a) is optionally substituted

In some embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R^(a) is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl. In someembodiments, R^(a) is 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl optionally substituted with one ormore —(C₁₋₆ alkylene)OH, —CN, —OH, or —O(C₁₋₆ alkyl). In someembodiments, R^(a) is 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl optionally substituted with one ormore —CH₂OH, —CN, —OH, or —OCH₃. In some embodiments, R^(a) isoptionally substituted C₃₋₆ cycloalkyl. In some embodiments, R^(a) isC₃₋₆ cycloalkyl optionally substituted with one or more —(C₁₋₆alkylene)OH, —CN, —OH, or —O(C₁₋₆ alkyl). In some embodiments, R^(a) isC₃₋₆ cycloalkyl optionally substituted with one or more —CH₂OH, —CN,—OH, or —OCH₃. In some embodiments, R^(a) is optionally substituted C₃cycloalkyl. In some embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted C₄ cycloalkyl. Insome embodiments, R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted C₅ cycloalkyl. Insome embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted C₆ cycloalkyl. Insome embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(a) is 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more oxo, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), or —O(C₁₋₄ alkyl). Insome embodiments, R^(a) is 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more oxo, C₁₋₄ alkyl optionally substituted with one or morehalogen, —C(O)(C₁₋₄ alkyl), or —O(C₁₋₄ alkyl). In some embodiments,R^(a) is 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur optionally substituted with one or moreoxo, halogen, —C(O)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), or C₁₋₄ alkyloptionally substituted with one or more halogen and —O(C₁₋₄ alkyl). Insome embodiments, R^(a) is 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more oxo, C₁₋₂ alkyl, —C(O)CH₃, or —OCH₃. In some embodiments,R^(a) is 3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur optionally substituted with one or moreoxo, C₁₋₂ alkyl optionally substituted with one or more fluoro,—C(O)CH₃, or —OCH₃. In some embodiments, R^(a) is 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfuroptionally substituted with one or more oxo, fluoro, —C(O)CH₃, —OCH₃, orC₁₋₂ alkyl optionally substituted with one or more fluoro and —OCH₃. Insome embodiments, R^(a) is optionally substituted 3- to 6-memberedsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(a)is 3- to 6-membered saturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfuroptionally substituted with one or more oxo, C₁₋₄ alkyl, —C(O)(C₁₋₄alkyl), or —O(C₁₋₄ alkyl). In some embodiments, R^(a) is 3- to6-membered saturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur optionallysubstituted with one or more oxo, C₁₋₄ alkyl optionally substituted withone or more halogen, —C(O)(C₁₋₄ alkyl), or —O(C₁₋₄ alkyl). In someembodiments, R^(a) is 3- to 6-membered saturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur optionally substituted with one or more oxo, halogen, —C(O)(C₁₋₄alkyl), —O(C₁₋₄ alkyl), or C₁₋₄ alkyl optionally substituted with one ormore halogen and —O(C₁₋₄ alkyl). In some embodiments, R^(a) is 3- to6-membered saturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur optionallysubstituted with one or more oxo, C₁₋₂ alkyl, —C(O)CH₃, or —OCH₃. Insome embodiments, R^(a) is 3- to 6-membered saturated monocyclicheterocyclyl having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur optionally substituted with one or moreoxo, C₁₋₂ alkyl optionally substituted with one or more fluoro,—C(O)CH₃, or —OCH₃. In some embodiments, R^(a) is 3- to 6-memberedsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more oxo, fluoro, —C(O)CH₃, —OCH₃, or C₁₋₂ alkyl optionallysubstituted with one or more fluoro and —OCH₃. In some embodiments,R^(a) is 3- to 6-membered saturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(a) is 3- to 6-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(a) is optionallysubstituted 3-membered saturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(a) is optionally substituted 3-membered saturatedmonocyclic heterocyclyl having 1 heteroatom independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(a) is optionallysubstituted 4-membered saturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(a) is optionally substituted 4-membered saturatedmonocyclic heterocyclyl having 1 heteroatom independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(a) is optionallysubstituted azetidinyl or oxetanyl. In some embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted 5-memberedsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(a)is 5-membered saturated monocyclic heterocyclyl having 1 heteroatomindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(a) is optionally substituted pyrrolidinyl ortetrahydrofuranyl. In some embodiments, R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is optionally substituted 6-memberedsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(a)is optionally substituted 6-membered saturated monocyclic heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R^(a) is optionally substitutedpiperizinyl, morpholinyl, tetrahydropyranyl, or 1,4-dioxanyl. In someembodiments, R^(a) is optionally substituted piperidinyl, piperizinyl,morpholinyl, tetrahydropyranyl, or 1,4-dioxanyl. In some embodiments,R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is not

In some embodiments, R^(a) is not

In some embodiments, R^(a) is optionally substituted 7- to 10-memberedsaturated or partially unsaturated bicyclic heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(a) is 7- to 10-membered saturated or partiallyunsaturated bicyclic heterocyclyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more —C(O)(C₁₋₄ alkyl). In some embodiments, R^(a) is 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur optionally substituted with one or more —C(O)CH₃. In someembodiments, R^(a) is optionally substituted 7- to 10-memberedsaturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(a) is optionally substituted 7- to 8-membered saturated,spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(a)is 7- to 8-membered saturated, spirocyclic, bicyclic heterocyclyl having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R^(a) is 7- to 10-membered saturated,spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more —C(O)(C₁₋₄ alkyl). In some embodiments, R^(a) is 7- to10-membered saturated, spirocyclic, bicyclic heterocyclyl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfuroptionally substituted with one or more —C(O)CH₃. In some embodimentsR^(a) is optionally substituted 7-membered saturated, spirocyclic,bicyclic heterocyclyl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments R^(a) is optionallysubstituted 7-membered saturated, spirocyclic, bicyclic heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R^(a) is optionally substituted2-oxaspiro[3.3]heptanyl or 2-azaspiro[3.3]heptanyl. In some embodiments,R^(a) is optionally substituted 2-oxaspiro[3.3]heptanyl,2-azaspiro[3.3]heptanyl, or 4-oxaspiro[2.4]heptanyl. In someembodiments, R^(a) is

In some embodiments, R^(a) is

In some embodiments, R^(a) is selected from the group consisting of:

In some embodiments, R^(a) is not fluoro, chloro, bromo, —CF₃,

In some embodiments, R^(a) is not chloro, bromo, or

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E,

is —R^(a) (i.e., L is a covalent bond). In some embodiments,

is —(C₁₋₃ alkylene)-R^(a) (i.e., L is a C₁₋₃ straight or branchedhydrocarbon chain). In some embodiments,

is —(C₁₋₂ alkylene)-R^(a) (i.e., L is a C₁₋₂ straight or branchedhydrocarbon chain). In some embodiments

is —CH₂—R^(a) (i.e., L is a C₁ hydrocarbon chain). In some embodiments,

is —CH₂CH₂—R^(a) (i.e., L is a C₂ straight hydrocarbon chain). In someembodiments,

is —CH₂CH₂CH₂—R^(a) (i.e., L is a C₃ straight hydrocarbon chain).

In some embodiments of any of Formulae I′, II′, III′, IV′, I-B, II-B,III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E,III-E, and IV-E, up to five occurrences of R^(b) may be present, asallowed by valency rules, and is each independently halogen, —CN, —OR,—SR, —N(R)₂, —NO₂, —C(O)R′, —C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂,—OC(O)OR, —OSO₂R, —OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′,—SO₂N(R)₂, —SO₃R′, optionally substituted C₁₋₆ aliphatic, optionallysubstituted 3- to 6-membered saturated or partially unsaturatedcarbocyclyl, optionally substituted 3- to 6-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, optionallysubstituted 5- to 6-membered monocyclic heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, each occurrence of R^(b) is independently hydrogen,halogen, optionally substituted C₁₋₄ alkyl, optionally substituted C₃₋₄cycloalkyl, optionally substituted 3- to 5-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or optionallysubstituted 5-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(b) is halogen, optionally substituted C₁₋₄ alkyl oroptionally substituted C₃₋₄ cycloalkyl. In some embodiments, R^(b) isoptionally substituted C₁₋₄ alkyl or optionally substituted C₃₋₄cycloalkyl. In some embodiments, R^(b) is C₃₋₄ cycloalkyl or C₁₋₄ alkyloptionally substituted with one or more fluoro.

In some embodiments, R^(b) is hydrogen.

In some embodiments, R^(b) is halogen. In some embodiments, R^(b) isfluoro, chloro, bromo, or iodo. In some embodiments, R^(b) is fluoro. Insome embodiments, R^(b) is chloro. In some embodiments, R^(b) is nothalogen. In some embodiments, R^(b) is not fluoro. In some embodiments,R^(b) is not chloro.

In some embodiments, R^(b) is —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,—C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,—OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R, —SO₂N(R)₂, or —SO₃R′. Insome embodiments, R^(b) is —CN, —SR, —N(R)₂, —NO₂, —C(O)R′, —C(O)OR,—C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R, —OSO₂N(R)₂,—N(R)C(O)R′, —N(R)SO₂R′, —SO₂R, —SO₂N(R)₂, or —SO₃R′. In someembodiments, R^(b) is not —OR. In some embodiments, R^(b) is not

In some embodiments, R^(b) is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R^(b) is optionally substituted straight-chain orbranched C₁₋₆ aliphatic (i.e., optionally substituted acyclic C₁₋₆aliphatic). In some embodiments, R^(b) is optionally substituted C₁₋₆alkyl. In some embodiments, R^(b) is optionally substituted C₁₋₄ alkyl.In some embodiments, R^(b) is C₁₋₄ alkyl optionally substituted with oneor more halogen. In some embodiments, R^(b) is C₁₋₄ alkyl optionallysubstituted with one or more of halogen and —CN. In some embodiments,R^(b) is methyl. In some embodiments, R^(b) is —CF₃. In someembodiments, R^(b) is tert-butyl. In some embodiments, R^(b) is —CF₂CF₃.In some embodiments, R^(b) is —C(CH₃)₂CN.

In some embodiments, R^(b) is optionally substituted 3- to 6-memberedsaturated or partially unsaturated carbocyclyl. In some embodiments,R^(b) is optionally substituted C₃₋₆ cycloalkyl. In some embodiments,R^(b) is cyclopropyl. In some embodiments, R^(b) is cyclobutyl.

In some embodiments, R^(b) is optionally substituted 3- to 6-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R^(b) is optionally substituted 3- to 6-memberedsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(b)is optionally substituted 3- to 5-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R^(b)is azetidinyl.

In some embodiments, R^(b) is optionally substituted 5- to 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R^(b) is optionallysubstituted 5-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R^(b) is pyrazolyl.

In some embodiments, R^(b) is not fluoro, chloro, bromo, —OR, or —CF₃.In some embodiments, R^(b) is not fluoro, chloro, bromo,

In some embodiments, R^(b) is not chloro, bromo, or —OR. In someembodiments, R^(b) is not chloro, bromo,

In some embodiments of any of Formulae I, II, III, IV, I-A, II-A, III-A,and IV-A, optionally substituted

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is an optionally substituted group selected from:

In some embodiments, optionally substituted

is optionally substituted

In some embodiments,

is selected from:

In some embodiments,

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is selected from:

In some embodiments,

is:

In some embodiments,

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is:

In some embodiments,

is not:

In some embodiments,

is not:

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E, each Ris independently hydrogen or optionally substituted C₁₋₆ aliphatic. Insome embodiments, each R is independently hydrogen or optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R is independentlyhydrogen or C₁₋₆ alkyl. In some embodiments, each R is independentlyhydrogen or optionally substituted C₁₋₄ alkyl. In some embodiments, eachR is independently hydrogen or C₁₋₄ alkyl. In some embodiments, each Ris independently hydrogen or methyl.

In some embodiments, R is hydrogen.

In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is optionally substituted straight-chain or branched C₁₋₆aliphatic (i.e., optionally substituted acyclic C₁₋₆ aliphatic). In someembodiments, R is optionally substituted C₁₋₆ alkyl. In someembodiments, R is optionally substituted C₁₋₄ alkyl. In someembodiments, R is unsubstituted C₁₋₄ alkyl. In some embodiments, R isoptionally substituted C₁₋₂ alkyl. In some embodiments, R isunsubstituted C₁₋₂ alkyl. In some embodiments, R is methyl.

In some embodiments, R is optionally substituted 3- to 7-memberedsaturated or partially unsaturated carbocyclyl.

In some embodiments, R is optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, two R when attached to the same nitrogen atom aretaken together form a 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 0-2 additional heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, two R groups when attached to the same nitrogen are takentogether to form a 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 0-2 additional heteroatoms independentlyselected from nitrogen, oxygen, and sulfur optionally substituted withone or more halogen, C₁₋₆ alkyl, and —O(C₁₋₆ alkyl). In someembodiments, two R groups when attached to the same nitrogen are takentogether to form an optionally substituted 3- to 5-membered saturatedmonocyclic heterocyclyl having 0-1 additional heteroatoms. In someembodiments, two R groups when attached to the same nitrogen are takentogether to form an optionally substituted 4-membered saturatedmonocyclic heterocyclyl having 0-1 additional heteroatoms. In someembodiments, two R groups when attached to the same nitrogen are takentogether to form a 3- to 5-membered saturated monocyclic heterocyclylhaving 0-1 additional heteroatoms optionally substituted with one ormore halogen, C₁₋₆ alkyl, and —O(C₁₋₆ alkyl). In some embodiments, two Rgroups when attached to the same nitrogen are taken together to form a4-membered saturated monocyclic heterocyclyl having 0-1 additionalheteroatoms optionally substituted with one or more halogen, C₁₋₆ alkyl,and —O(C₁₋₆ alkyl).

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C,III-C, IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E, each R′is independently optionally substituted C₁₋₆ alkyl or optionallysubstituted C₃₋₆ cycloalkyl. In some embodiments, each R′ isindependently optionally substituted C₁₋₂ alkyl or optionallysubstituted C₃₋₄ cycloalkyl. In some embodiments, each R′ isindependently methyl or optionally substituted C₃ cycloalkyl. In someembodiments, each R′ is independently C₁₋₂ alkyl or C₃₋₄ cycloalkyl. Insome embodiments, each R′ is independently methyl or cycloproyl. In someembodiments, each R′ is independently methyl,

In some embodiments, each R′ is independently methyl, —CH₂CH₂OCH₃,

In some embodiments, each R′ is independently methyl, —CH₂CH₂OCH₃,

In some embodiments, R′ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R′ is optionally substituted straight-chain orbranched C₁₋₆ aliphatic (i.e., optionally substituted acyclic C₁₋₆aliphatic). In some embodiments, R′ is optionally substituted C₁₋₆alkyl. In some embodiments, R′ is C₁₋₆ alkyl optionally substituted with—OC₁₋₆ alkyl or a 3- to 7-membered saturated monocyclic heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, R′ is optionally substituted C₁₋₄ alkyl. Insome embodiments, R′ is C₁₋₄ alkyl optionally substituted with —OC₁₋₆alkyl or a 3- to 7-membered saturated monocyclic heterocyclyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R′ is unsubstituted C₁₋₄ alkyl. In some embodiments,R′ is optionally substituted C₁₋₂ alkyl. In some embodiments, R′ is C₁₋₂alkyl optionally substituted with —OC₁₋₆ alkyl or a 3- to 7-memberedsaturated monocyclic heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In some embodiments, R′ isunsubstituted C₁₋₂ alkyl. In some embodiments, R′ is methyl. In someembodiments, R′ is —CH₂CH₂OCH₃. In some embodiments, R′ is C₁₋₂ alkyloptionally substituted with a 3- to 7-membered saturated monocyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur (e.g., morpholinyl or tetrahydopyranyl).

In some embodiments, R′ is optionally substituted C₁₋₆ aliphatic oroptionally substituted 3- to 7-membered saturated or partiallyunsaturated carbocyclyl. In some embodiments, R′ is 3- to 7-memberedsaturated or partially unsaturated carbocyclyl optionally substitutedwith one or more halogen. In some embodiments, R′ is optionallysubstituted C₃₋₆ cycloalkyl. In some embodiments, R′ is C₃₋₆ cycloalkyloptionally substituted with one or more halogen. In some embodiments, R′is optionally substituted C₃ cycloalkyl. In some embodiments, R′ is

In some embodiments, R′ is

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, the compound is not:

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, the compound is not:

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, the compound is not:

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′ and R′ isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl), then Ring A is notphenyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′ and R′ ismethyl, then Ring A is not phenyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′, R′ isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl), and Ring A is phenyl,then R^(a) is not fluoro.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′, R′ isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl), and Ring A is phenyl,then R^(a) is not —CF₃ or optionally substituted piperazinyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′, R′ isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl), and Ring A is phenyl,then R^(a) is not —CF₃ or

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —N(H)C(O)R′, R′ isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl), and Ring A is phenyl,then R^(b) is not —CF₃ or

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R) and R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), then RingA is not phenyl.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R), R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), and RingA is phenyl, then neither R^(a) nor R^(b) is chloro or bromo.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R), R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), and RingA is phenyl, then R^(a) is not chloro or bromo.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R), R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), and RingA is phenyl, then R^(x) is not

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R), R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), and RingA is phenyl, then R^(b) is not —OR.

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when R¹ is —C(O)NH(R), R isoptionally substituted C₁₋₆ aliphatic (e.g., optionally substituted C₁₋₆alkyl, e.g., optionally substituted C₁₋₂ alkyl, e.g., methyl), and RingA is phenyl, then R^(b) is not

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when Ring A is phenyl, R¹ is—NHC(O)R′ or —NH₂, R² is —CH₃, X is CH, and R′ is optionally substitutedC₁₋₂ aliphatic, then R^(a) and R^(b) are not fluoro or

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when Ring A is phenyl, R¹ is—NHC(O)CH₃, R² is —CH₃, and X is N, then R^(a) and R^(b) are not fluoroor

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when Ring A is phenyl, R¹ is—NHC(O)CH₃, R² is —CH₃, and X is CCH₃, then R^(a) and R^(b) are not

In some embodiments of any of Formulae I-1, I, II, III, IV, I′, II′,III′, IV′, I-A, II-A, III-A, and IV-A, when Ring A is phenyl, R¹ is—C(O)NHCH₃, R² is C₁₋₂ alkyl, and X is CH, then R^(a) and R^(b) are nothalogen.

In some embodiments, the present disclosure provides compounds selectedfrom Table 1:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure encompasses the recognitionthat provided compounds display certain desirable characteristics, e.g.,as compared to other known compounds. For example, in some embodiments,provided compounds are more potent in one or more biochemical orcellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 CellularAssay described herein) and/or have one or more other characteristicsthat make them more suitable for drug development, such as betterselectivity over other kinases and/or better ADME (absorption,distribution, metabolism, and excretion) properties including but notlimited to better permeability, cytotoxicity, hepatocyte stability,solubility, and/or plasma protein binding profiles (e.g., based onassays described in the ensuing examples), than other known compounds.In some embodiments, provided compounds display certain desirablecharacteristics in one or more assays described herein, e.g., comparedto other known compounds. Without wishing to be bound by any particulartheory, the present disclosure encompasses the recognition that6-heteroaryloxy benzimidazoles and azabenzimidazoles (e.g., compoundsdescribed herein) display certain more desirable characteristics (suchas better properties in one or more assays described herein) thancorresponding 5-heteroaryloxy benzimidazoles and azabenzimidazoles.

In some embodiments, provided compounds are provided and/or utilized ina salt form (e.g., a pharmaceutically acceptable salt form). Referenceto a compound provided herein is understood to include reference tosalts thereof, unless otherwise indicated. Pharmaceutically acceptablesalt forms are known in the art. For example, S. M. Berge, et al.describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19(1977).

It will be appreciated that throughout the present disclosure, unlessotherwise indicated, reference to a compound of Formula I-1 is intendedto also include Formulae I, I′, II′, III′, IV′, II, III, IV, I-A, II-A,III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C, I-D, II-D,III-D, IV-D, I-E, II-E, III-E, and IV-E, and compound species of suchformulas disclosed herein.

Preparing Provided Compounds

In some embodiments, provided compounds (e.g., compounds of Formula I-1wherein Z is —NH—) are prepared according to the following Scheme:

wherein Ring A, L, W, X, Y, R¹, R², and R^(a) are as defined above forFormula I-1. Accordingly, in some embodiments, intermediate A.2 isprepared by a process comprising contacting intermediate A.1 withthiophosgene in the presence of a suitable base (e.g., NaHCO₃ ortriethylamine). In some embodiments, compound A-1 is prepared by aprocess comprising contacting intermediate A.2 with intermediate A.3-1in the presence of a suitable coupling agent (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride orN,N′-diisopropylcarbodiimide).

In some embodiments, provided compounds (e.g., compounds of Formula Iwherein Z is —NH—) are prepared according to the following Scheme:

wherein Ring A, L, X, Y, R¹, R², and R^(a) are as defined above forFormula I. Accordingly, in some embodiments, intermediate A.2 isprepared by a process comprising contacting intermediate A.1 withthiophosgene in the presence of a suitable base (e.g., NaHCO₃ ortriethylamine). In some embodiments, compound A is prepared by a processcomprising contacting intermediate A.2 with intermediate A.3 in thepresence of a suitable coupling agent (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride orN,N′-diisopropylcarbodiimide).

In some embodiments, provided compounds (e.g., compounds of Formula I-1wherein Z is —O—) are prepared according to the following Scheme:

wherein LG is a suitable leaving group (e.g., halogen, e.g., chloro) andRing A, L, W, X, Y, R¹, R², and R^(a) are as defined above for FormulaI-1. Accordingly, in some embodiments, compound B-1 is prepared by aprocess comprising contacting intermediate B.1-1 with intermediate B.2in the presence of a suitable base (e.g., K₂CO₃).

In some embodiments, provided compounds (e.g., compounds of Formula I-1wherein Z is —O—) are prepared according to the following Scheme:

wherein LG is a suitable leaving group (e.g., halogen, e.g., chloro) andRing A, L, X, Y, R¹, R², and R^(a) are as defined above for Formula I.Accordingly, in some embodiments, compound B is prepared by a processcomprising contacting intermediate B.1 with intermediate B.2 in thepresence of a suitable base (e.g., K₂CO₃).

In some embodiments, a provided compound is obtained by a processcomprising a purification method described in the Examples section. Insome such embodiments, a compound is the 1^(st) eluting isomer. In somesuch embodiments, a compound is the 2^(nd) eluting isomer. In someembodiments, a compound is the 3^(rd) eluting isomer. In someembodiments, a compound is the 4^(th) eluting isomer. In someembodiments, a compound is the 5^(th), 6^(th), 7^(th), 8^(th), or moreeluting isomer.

Compositions

The present disclosure also provides compositions comprising a compoundprovided herein with one or more other components. In some embodiments,provided compositions comprise and/or deliver a compound describedherein (e.g., compounds of Formulae I-1, I, II, III, IV, I′, II′, III′,IV′, I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C,IV-C, I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E).

In some embodiments, a provided composition is a pharmaceuticalcomposition that comprises and/or delivers a compound provided herein(e.g., compounds of Formulae I-1, I, II, III, IV, I′, II′, III′, IV′,I-A, II-A, III-A, IV-A, I-B, II-B, III-B, IV-B, I-C, II-C, III-C, IV-C,I-D, II-D, III-D, IV-D, I-E, II-E, III-E, and IV-E) and furthercomprises a pharmaceutically acceptable carrier. Pharmaceuticalcompositions typically contain an active agent (e.g., a compounddescribed herein) in an amount effective to achieve a desiredtherapeutic effect while avoiding or minimizing adverse side effects. Insome embodiments, provided pharmaceutical compositions comprise acompound described herein and one or more fillers, disintegrants,lubricants, glidants, anti-adherents, and/or anti-statics, etc. Providedpharmaceutical compositions can be in a variety of forms including oraldosage forms, topical creams, topical patches, iontophoresis forms,suppository, nasal spray and/or inhaler, eye drops, intraocularinjection forms, depot forms, as well as injectable and infusiblesolutions. Methods of preparing pharmaceutical compositions are wellknown in the art.

In some embodiments, provided compounds are formulated in a unit dosageform for ease of administration and uniformity of dosage. The expression“unit dosage form” as used herein refers to a physically discrete unitof an active agent (e.g., a compound described herein) foradministration to a subject. Typically, each such unit contains apredetermined quantity of active agent. In some embodiments, a unitdosage form contains an entire single dose of the agent. In someembodiments, more than one unit dosage form is administered to achieve atotal single dose. In some embodiments, administration of multiple unitdosage forms is required, or expected to be required, in order toachieve an intended effect. A unit dosage form may be, for example, aliquid pharmaceutical composition containing a predetermined quantity ofone or more active agents, a solid pharmaceutical composition (e.g., atablet, a capsule, or the like) containing a predetermined amount of oneor more active agents, a sustained release formulation containing apredetermined quantity of one or more active agents, or a drug deliverydevice containing a predetermined amount of one or more active agents,etc.

Provided compositions may be administered using any amount and any routeof administration effective for treating or lessening the severity ofany disease or disorder described herein.

Uses

The present disclosure provides uses for compounds and compositionsdescribed herein. In some embodiments, provided compounds andcompositions are useful in medicine (e.g., as therapy). In someembodiments, provided compounds and compositions are useful in researchas, for example, analytical tools and/or control compounds in biologicalassays.

In some embodiments, the present disclosure provides methods ofadministering provided compounds or compositions to a subject in needthereof. In some embodiments, the present disclosure provides methods ofadministering provided compounds or compositions to a subject sufferingfrom or susceptible to a disease, disorder, or condition associated withJAK2.

In some embodiments, provided compounds are useful as JAK2 inhibitors.In some embodiments, provided compounds are useful as Type II JAK2inhibitors. In some embodiments, the present disclosure provides methodsof inhibiting JAK2 in a subject comprising administering a providedcompound or composition. In some embodiments, the present disclosureprovides methods of inhibiting JAK2 in a biological sample comprisingcontacting the sample with a provided compound or composition.

JAK (e.g., JAK2) has been implicated in various diseases, disorders, andconditions, such as myeloproliferative neoplasms (Vainchenker, W. etal., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis(Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40.)and acute respiratory syndrome, hyperinflammation, and/or cytokine stormsyndrome (The Lancet. doi:10.1016/S0140-6736(20)30628-0). Accordingly,in some embodiments, the present disclosure provides methods of treatinga disease, disorder or condition associated with JAK2 in a subject inneed thereof comprising administering to the subject a provided compoundor composition. In some embodiments, a disease, disorder or condition isassociated with overexpression of JAK2.

In some embodiments, the present disclosure provides methods of treatingcancer, comprising administering a provided compound or composition to asubject in need thereof. In some embodiments, the present disclosureprovides methods of treating proliferative diseases, comprisingadministering a provided compound or composition to a subject in needthereof.

In some embodiments, the present disclosure provides methods of treatinga hematological malignancy, comprising administering a provided compoundor composition to a subject in need thereof. In some embodiments, ahematological malignancy is leukemia (e.g., chronic lymphocyticleukemia, acute lymphoblastic leukemia, T-cell acute lymphoblasticleukemia, chronic myelogenous leukemia, acute myelogenous leukemia, oracute monocytic leukemia). In some embodiments, a hematologicalmalignancy is lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, ornon-Hodgkin's lymphoma). In some embodiments, a non-Hodgkin's lymphomais a B-cell lymphoma. In some embodiments, a non-Hodgkin's lymphoma is aNK/T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In someembodiments, a hematological malignancy is myeloma (e.g., multiplemyeloma). In some embodiments, a hematological malignancy ismyeloproliferative neoplasm (e.g., polycythemia vera, essentialthrombocytopenia, or myelofibrosis). In some embodiments, ahematological malignancy is myelodysplastic syndrome.

In some embodiments, the present disclosure provides methods of treatingan inflammatory disease, disorder, or condition (e.g., acute respiratorysyndrome, hyperinflammation, and/or cytokine storm syndrome (includingthose associated with COVID-19) or atopic dermatitis), comprisingadministering a provided compound or composition to a subject in needthereof.

In some embodiments, a provided compound or composition is administeredas part of a combination therapy. As used herein, the term “combinationtherapy” refers to those situations in which a subject is simultaneouslyexposed to two or more therapeutic or prophylactic regimens (e.g., twoor more therapeutic or prophylactic agents). In some embodiments, thetwo or more regimens may be administered simultaneously; in someembodiments, such regimens may be administered sequentially (e.g., all“doses” of a first regimen are administered prior to administration ofany doses of a second regimen); in some embodiments, such agents areadministered in overlapping dosing regimens. In some embodiments,“administration” of combination therapy may involve administration ofone or more agent(s) or modality(ies) to a subject receiving the otheragent(s) or modality(ies) in the combination. For clarity, combinationtherapy does not require that individual agents be administered togetherin a single composition (or even necessarily at the same time), althoughin some embodiments, two or more agents, or active moieties thereof, maybe administered together in a combination composition.

For example, in some embodiments, a provided compound or composition isadministered to a subject who is receiving or has received one or moreadditional therapies (e.g., an anti-cancer therapy and/or therapy toaddress one or more side effects of such anti-cancer therapy, orotherwise to provide palliative care). Exemplary additional therapiesinclude, but are not limited to, BCL2 inhibitors (e.g., venetoclax),HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib),proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g.,IMG-7289), and CXCR2 inhibitors. Useful combinations of a JAK2 inhibitorwith BCL2, HDAC, BET, and proteasome inhibitors have been demonstratedin cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., etal., Blood Adv. 2020, 4(10), 2213-2226). A combination of a JAK2inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mousemodel of myeloproliferative neoplasms (Jutzi, J. S., et al., HemaSphere2018, 2(3), dx.doi.org/10.1097/HS9.0000000000000054). CXCR2 activity hasbeen shown to modulate signaling pathways involved in tumor growth,angiogenesis, and/or metastasis, including the JAK-STAT3 pathway(Jaffer, T., Ma, D. Transl. Cancer Res. 2016, 5(Suppl. 4), S616-S628).

Exemplary Embodiments

The following numbered embodiments, while non-limiting, are exemplary ofcertain aspects of the present disclosure:

A1. A compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x), and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form an optionally substituted 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 0-2 additional heteroatoms independently    selected from nitrogen, oxygen, and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.    A2. The compound of embodiment A1, wherein:-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x), and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form a 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 0-2    additional heteroatoms independently selected from nitrogen, oxygen,    and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.    A3. The compound of embodiment A1 or A2, wherein:-   W is CH;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(x) and R^(y) are each independently hydrogen, optionally    substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted phenyl, optionally substituted 5-    to 6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic carbocyclyl, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7- to    10-membered saturated or partially unsaturated bicyclic heterocyclyl    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form a 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 0-2    additional heteroatoms independently selected from nitrogen, oxygen,    and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.    A4. The compound of any one of the preceding embodiments, wherein    the compound is not:

A5. The compound of any one of the preceding embodiments, wherein Ring Ais optionally substituted 5- to 6-membered monocyclic heteroaryl having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 8- to 10-membered bicyclic heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, optionally substituted 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or optionally substituted 7- to 10-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.A5. The compound of any one of the preceding embodiments, wherein Ring Ais optionally substituted 5- to 6-membered monocyclic heteroaryl having1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.A6. The compound of any one of the preceding embodiments, wherein R^(a)is halogen, optionally substituted C₁₋₄ alkyl, optionally substituted5-membered monocyclic heteroaryl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, optionally substituted 3- to6-membered saturated monocyclic carbocyclyl, optionally substituted 3-to 6-membered saturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or optionallysubstituted 7-membered saturated, spirocyclic, bicyclic heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.A7. The compound of any one of the preceding embodiments, wherein:

and

-   R^(b) hydrogen, halogen, —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,    —C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,    —OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′, —SO₂N(R)₂, —SO₃R′,    optionally substituted C₁₋₆ aliphatic, optionally substituted 3- to    6-membered saturated or partially unsaturated carbocyclyl,    optionally substituted 3- to 6-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 5- to 6-membered monocyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.    A8. The compound of embodiment A7, wherein

A9. The compound of embodiment A7 or A8, wherein R^(b) is halogen,optionally substituted C₁₋₄ alkyl or optionally substituted C₃₋₄cycloalkyl.A10. The compound of any one of the preceding embodiments, wherein R¹ is—N(R)₂.A11. The compound of embodiment A10, wherein R¹ is —N(H)(R).A12. The compound of any one of embodiments A1-A9, wherein R¹ is—N(R)C(O)R′.A13. The compound of embodiment A12, wherein R¹ is —N(H)C(O)R′.A14. The compound of embodiment A13, wherein R¹ is —N(H)C(O)CH₃.A15. The compound of any one of embodiments A1-A9, wherein R¹ is—C(O)N(R)₂.A16. The compound of embodiment A15, wherein R¹ is —C(O)N(H)CH₃.A17. The compound of any one of embodiments A1-A9, wherein R¹ is—N(R)C(O)N(R)₂.A18. The compound of embodiment A17, wherein R¹ is —N(H)C(O)N(R)₂.A19. The compound of any one of the preceding embodiments, wherein R² isC₁₋₄ alkyl.A20. The compound of any one of the preceding embodiments, wherein X isCR^(x).A21. The compound of embodiment A20, wherein R^(x) is hydrogen, halogen,—OR³, optionally substituted C₁₋₆ aliphatic, or —CN.A22. The compound of embodiment A21, wherein R^(x) is hydrogen.A23. The compound of any one of embodiments A1-A19, wherein X is N.A24. The compound of any one of the preceding embodiments, wherein Y isCR^(y).A25. The compound of embodiment A24, wherein R^(y) is hydrogen.A26. The compound of any one of embodiments A1-A23, wherein Y is N.A27. The compound of any one of the preceding embodiments, wherein Z isNR^(z)—.A28. The compound of embodiment 27, wherein R^(z) is hydrogen.A29. The compound of any one of embodiments A1-A26, wherein Z is —O—.A30. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-A:

or a pharmaceutically acceptable salt thereof.A31. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-B:

or a pharmaceutically acceptable salt thereof.A32. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-C:

or a pharmaceutically acceptable salt thereof.A33. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-D:

or a pharmaceutically acceptable salt thereof.A34. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-E:

or a pharmaceutically acceptable salt thereof.A35. The compound of embodiment 1, wherein the compound is a compound ofTable 1.A36. A pharmaceutical composition comprising a compound of any one ofthe preceding embodiments, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.A37. A method of inhibiting JAK2 in a subject comprising administeringthe compound of any one of embodiments A1-A35 or the composition ofembodiment A36.A38. A method of treating a disease, disorder, or condition associatedwith JAK2, comprising administering to a subject in need thereof thecompound of any one of embodiments A1-A35 or the composition ofembodiment A36.A39. A method of treating cancer, comprising administering to a subjectin need thereof the compound of any one of embodiments A1-A35 or thecomposition of embodiment A36.A40. A method of treating a hematological malignancy, comprisingadministering to a subject in need thereof the compound of any one ofembodiments A1-A35 or the composition of embodiment A36.A41. The method of embodiment A40, wherein the hematological malignancyis leukemia or lymphoma.A42. A method of treating a myeloproliferative neoplasm, comprisingadministering to a subject in need thereof the compound of any one ofembodiments A1-A35 or the composition of embodiment A36.A43. The method of embodiment A42, wherein the myeloproliferativeneoplasm is polycythemia vera, essential thrombocytopenia ormyelofibrosis.B1. A compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x), and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted 5- to 6-membered monocyclic    heteroaryl having 1-4 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, optionally substituted 8- to    10-membered bicyclic heteroaryl having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, optionally substituted    3- to 7-membered saturated or partially unsaturated monocyclic    carbocyclyl, optionally substituted 3- to 7-membered saturated or    partially unsaturated monocyclic heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or    optionally substituted 7- to 10-membered saturated or partially    unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form an optionally substituted 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 0-2 additional heteroatoms independently    selected from nitrogen, oxygen, and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.    B2. The compound of embodiment B1, wherein Ring A is optionally    substituted 5- to 6-membered monocyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.    B3. The compound of embodiment B1, wherein Ring A is optionally    substituted 8- to 10-membered bicyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.    B4. The compound of embodiment B1, wherein Ring A is optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl.    B5. The compound of embodiment B1, wherein Ring A is optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic heterocyclyl having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur.    B6. The compound of embodiment B1, wherein Ring A is optionally    substituted 7- to 10-membered saturated or partially unsaturated    bicyclic heterocyclyl having 1-4 heteroatoms independently selected    from nitrogen, oxygen, and sulfur.    B7. The compound of any one of the preceding embodiments, wherein    R^(a) is halogen, optionally substituted C₁₋₄ alkyl, optionally    substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 6-membered saturated monocyclic carbocyclyl,    optionally substituted 3- to 6-membered saturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7-membered    saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur.    B8. The compound of any one of the preceding embodiments, wherein    R^(a) is C₁₋₄ alkyl optionally substituted with one or more oxo,    halogen, —CN, —OH, or —O(C₁₋₆ alkyl).    B9. The compound of any one of the embodiments B1-B7, wherein R^(a)    is 3- to 6-membered saturated monocyclic carbocyclyl optionally    substituted with one or more —(C₁₋₆ alkylene)OH, —CN, —OH, or    —O(C₁₋₆ alkyl).    B10. The compound of any one of embodiments B1-B7, wherein R^(a) is    3- to 6-membered saturated monocyclic heterocyclyl having 1-3    heteroatoms independently selected from nitrogen, oxygen, and sulfur    optionally substituted with one or more oxo, halogen, —C(O)(C₁₋₄    alkyl), —O(C₁₋₄ alkyl), or C₁₋₄ alkyl optionally substituted with    one or more halogen and —O(C₁₋₄ alkyl).    B11. The compound of any one of embodiments B1-B7, wherein R^(a) is    optionally substituted 7- to 8-membered saturated, spirocyclic,    bicyclic heterocyclyl having 1-2 heteroatoms independently selected    from nitrogen, oxygen, and sulfur.    B12. The compound of any one of the preceding embodiments, wherein    R^(a) is C₁₋₄ alkyl, 3- to 6-membered saturated monocyclic    heterocyclyl having 1-2 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or 7- to 8-membered saturated,    spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur.    B13. The compound of any one of the preceding embodiments, wherein:

and

-   R^(b) hydrogen, halogen, —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,    —C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,    —OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′, —SO₂N(R)₂, —SO₃R′,    optionally substituted C₁₋₆ aliphatic, optionally substituted 3- to    6-membered saturated or partially unsaturated carbocyclyl,    optionally substituted 3- to 6-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 5- to 6-membered monocyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.

B14. The compound of embodiment B13, wherein

is:

B15. The compound of embodiment B13 or B14, wherein

is:

B16. The compound of any one of embodiments B13-B15, wherein R^(b) ishydrogen, halogen, optionally substituted C₁₋₄ alkyl, optionallysubstituted C₃₋₄ cycloalkyl, optionally substituted 3- to 5-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, oroptionally substituted 5-membered monocyclic heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.B17. The compound of any one of embodiments B13-B16, wherein R^(b) ishalogen, optionally substituted C₁₋₄ alkyl or optionally substitutedC₃₋₄ cycloalkyl.B18. The compound of any one of embodiments B13-B16, wherein R^(b) isC₃₋₄ cycloalkyl or C₁₋₄ alkyl optionally substituted with one or morefluoro.B19. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-B:

or a pharmaceutically acceptable salt thereof.B20. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-C:

or a pharmaceutically acceptable salt thereof.B21. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-D:

or a pharmaceutically acceptable salt thereof.B22. The compound of any one of the preceding embodiments, wherein thecompound is of Formula I-E:

or a pharmaceutically acceptable salt thereof.B23. A compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is CR^(w) or N;-   X is CR^(x) or N;-   Y is CR^(y) or N;-   Z is —O— or —NR^(z)—;-   R^(w), R^(x), and R^(y) are each independently hydrogen, halogen,    —OR³, —N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN;-   R^(z) is hydrogen or optionally substituted C₁₋₆ aliphatic;-   R¹ is —N(R)₂, —N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂;-   R² is optionally substituted C₁₋₆ aliphatic;-   R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;-   Ring A is optionally substituted phenyl;-   L is a covalent bond or a bivalent C₁₋₃ straight or branched    hydrocarbon chain;-   R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, optionally substituted 5- to    6-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 7-membered saturated or partially unsaturated    monocyclic carbocyclyl, optionally substituted 3- to 7-membered    saturated or partially unsaturated monocyclic heterocyclyl having    1-3 heteroatoms independently selected from nitrogen, oxygen, and    sulfur, or optionally substituted 7- to 10-membered saturated or    partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form an optionally substituted 3-    to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 0-2 additional heteroatoms independently    selected from nitrogen, oxygen, and sulfur; and-   each R′ is independently optionally substituted C₁₋₆ aliphatic or    optionally substituted 3- to 7-membered saturated or partially    unsaturated carbocyclyl.    B22. The compound of embodiment B21, wherein the compound is not:

B24. The compound of embodiment B22 or B23, wherein:

-   (i) if R¹ is —NHC(O)R′ or —NH₂, R² is —CH₃, X is CH, and R′ is    optionally substituted C₁₋₂ aliphatic, then R^(a) and R^(b) are not    fluoro or

-   (ii) if R¹ is —NHC(O)CH₃, R² is —CH₃, and X is N, then R^(a) and    R^(b) are not fluoro or

-   (iii) if R¹ is —NHC(O)CH₃, R² is —CH₃, and X is CCH₃, then R^(a) and    R^(b) are not

and

-   (iv) if R¹ is —C(O)NHCH₃, R² is C₁₋₂ alkyl, and X is CH, then R^(a)    and R^(b) are not halogen.    B25. The compound of any one of embodiments B22-B24, wherein R^(a)    is halogen, optionally substituted C₁₋₄ alkyl, optionally    substituted 5-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 3- to 6-membered saturated monocyclic carbocyclyl,    optionally substituted 3- to 6-membered saturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or optionally substituted 7-membered    saturated, spirocyclic, bicyclic heterocyclyl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur.    B26. The compound of any one of embodiments B22-B25, wherein R^(a)    is C₁₋₄ alkyl optionally substituted with one or more oxo, halogen,    —CN, —OH, or —O(C₁₋₆ alkyl).    B27. The compound of any one of embodiments B22-B25, wherein R^(a)    is 5-membered monocyclic heteroaryl having 1-4 heteroatoms    independently selected from nitrogen, oxygen, and sulfur optionally    substituted with one or more C₁₋₆ alkyl.    B28. The compound of any one of embodiments B22-B25, wherein R^(a)    is 3- to 7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur optionally substituted with one or more    oxo, halogen, —C(O)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), or C₁₋₄ alkyl    optionally substituted with one or more halogen and —O(C₁₋₄ alkyl).    B29. The compound of any one of embodiments B22-B28, wherein:

and

-   R^(b) hydrogen, halogen, —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,    —C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,    —OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′, —SO₂N(R)₂, —SO₃R′,    optionally substituted C₁₋₆ aliphatic, optionally substituted 3- to    6-membered saturated or partially unsaturated carbocyclyl,    optionally substituted 3- to 6-membered saturated or partially    unsaturated monocyclic heterocyclyl having 1-3 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, optionally    substituted 5- to 6-membered monocyclic heteroaryl having 1-4    heteroatoms independently selected from nitrogen, oxygen, and    sulfur.

B30. The compound of any one of embodiments B22-B29, wherein

is:

B31. The compound of embodiment B29 or B30, wherein R^(b) is halogen,optionally substituted C₁₋₄ alkyl or optionally substituted C₃₋₄cycloalkyl.B32. The compound of any one of the preceding embodiments, wherein L isa covalent bond or —CH₂—.B33. The compound of any one of the preceding embodiments, wherein R¹ is—N(R)₂.B34. The compound of any one of embodiments B1-B32, wherein R¹ is—N(H)(R).B35. The compound of any one of embodiments B1-B32, wherein R¹ is—N(R)C(O)R′.B36. The compound of any one of embodiments B1-B32, wherein R¹ is—N(H)C(O)R′.B37. The compound of any one of embodiments B1-B32, wherein R¹ is—N(H)C(O)(optionally substituted C₁₋₄ alkyl).B38. The compound of any one of embodiments B1-B32, wherein R¹ is—N(H)C(O)CH₃ or —N(H)C(O)(cyclopropyl).B39. The compound of any one of embodiments B1-B32, wherein R¹ is—C(O)N(R)₂.B40. The compound of any one of embodiments B1-B32, wherein R¹ is—C(O)N(H)CH₃.B41. The compound of any one of embodiments B1-B32, wherein R¹ is—N(R)C(O)N(R)₂.B42. The compound of any one of embodiments B1-B32, wherein R¹ is—N(H)C(O)N(R)₂.B43. The compound of any one of embodiments B1-B32, wherein R¹ is—N(R)C(O)N(R)₂, wherein the two R groups attached to the same nitrogenare taken together to form a 3- to 5-membered saturated monocyclicheterocyclyl having 0-1 additional heteroatoms optionally substitutedwith one or more halogen, C₁₋₆ alkyl, and —O(C₁₋₆ alkyl).B44. The compound of any one of the preceding embodiments, wherein R² isC₁₋₄ alkyl.B45. The compound of any one of the preceding embodiments, wherein R² ismethyl.B46. The compound of any one of the preceding embodiments, wherein X isCR^(x).B47. The compound of embodiment B46, wherein R^(x) is hydrogen, halogen,—OR³, optionally substituted C₁₋₆ aliphatic, or —CN.B48. The compound of embodiment B46, wherein R^(x) is halogen, —OR³, or—CN.B49. The compound of embodiment B46, wherein R^(x) is halogen, —OR³,—N(R³)₂, —SR³, or —CN.B50. The compound of any one of embodiments B1-B45, wherein X is N.B51. The compound of any one of the preceding embodiments, wherein Y isCR^(y).B52. The compound of embodiment B51, wherein R^(y) is hydrogen.B53. The compound of any one of embodiments B1-B50, wherein Y is N.B54. The compound of any one of the preceding embodiments, wherein W isCR^(w).B55. The compound of embodiment B54, wherein R^(w) is hydrogen.B56. The compound of any one of embodiments B1-B53, wherein W is N.B57. The compound of any one of the preceding embodiments, wherein Z is—NR^(z)—.B58. The compound of embodiment B57, wherein R^(z) is hydrogen.B59. The compound of any one of embodiments B1-B56, wherein Z is —O—.B60. The compound of any one of the preceding embodiments, wherein eachR is independently hydrogen, optionally substituted C₁₋₆ aliphatic,optionally substituted 3- to 7-membered saturated or partiallyunsaturated carbocyclyl, or optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R when attached to the same nitrogen atom are taken together form a3- to 7-membered saturated or partially unsaturated monocyclicheterocyclyl having 0-2 additional heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.B61. The compound of any one of the preceding embodiments, wherein eachR is independently hydrogen or optionally substituted C₁₋₆ aliphatic.B62. The compound of any one of the preceding embodiments, wherein eachR′ is independently optionally substituted C₁₋₂ alkyl or optionallysubstituted C₃₋₄ cycloalkyl.B63. The compound of any one of the preceding embodiments, wherein:

-   W is CH;-   R^(x) and R^(y) are each independently hydrogen, optionally    substituted C₁₋₆ aliphatic, or —CN;-   each R is independently hydrogen, optionally substituted C₁₋₆    aliphatic, optionally substituted 3- to 7-membered saturated or    partially unsaturated carbocyclyl, or optionally substituted 3- to    7-membered saturated or partially unsaturated monocyclic    heterocyclyl having 1-3 heteroatoms independently selected from    nitrogen, oxygen, and sulfur, or two R when attached to the same    nitrogen atom are taken together form a 3- to 7-membered saturated    or partially unsaturated monocyclic heterocyclyl having 0-2    additional heteroatoms independently selected from nitrogen, oxygen,    and sulfur.    B64. The compound of any one of the preceding embodiments, wherein    the compound is of Formula I-A:

or a pharmaceutically acceptable salt thereof.B65. A compound selected from Table 1, or a pharmaceutically acceptablesalt thereof.B66. A pharmaceutical composition comprising a compound of any one ofthe preceding embodiments, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.B67. A method of inhibiting JAK2 in a subject comprising administeringthe compound of any one of embodiments B1-B63 or the composition ofembodiment B64.B68. The method of embodiment B67, wherein the compound or compositionadministered is characterized in that it is a Type II inhibitor of JAK2.B69. A method of treating a disease, disorder, or condition associatedwith JAK2, comprising administering to a subject in need thereof thecompound of any one of embodiments B1-B65 or the composition ofembodiment B66.B70. A method of treating cancer, comprising administering to a subjectin need thereof the compound of any one of embodiments B1-B65 or thecomposition of embodiment B66.B71. A method of treating a hematological malignancy, comprisingadministering to a subject in need thereof the compound of any one ofembodiments B1-B65 or the composition of embodiment B66.B72. The method of embodiment B71, wherein the hematological malignancyis leukemia or lymphoma.B73. A method of treating a myeloproliferative neoplasm, comprisingadministering to a subject in need thereof the compound of any one ofembodiments B1-B65 or the composition of embodiment B66.B74. The method of embodiment B73, wherein the myeloproliferativeneoplasm is polycythemia vera, essential thrombocytopenia ormyelofibrosis.

EXAMPLES

As described in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present disclosure, the followinggeneral methods and other methods known to one of ordinary skill in theart can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Preparation of Intermediates Preparation of Intermediate Int-1:N-(4-Hydroxypyridin-2-yl)acetamide

Synthesis of compound Int-1.2. To a solution of benzyl alcohol (17.05 g,157.69 mmol, 1.0 equiv) in THF (250 mL) at 0° C. was added sodiumhydride (12.61 g, 315.38 mmol, 2.0 equiv) in small portions. The mixturewas stirred for 1 h and 2-chloro-4-nitropyridine (Int-1.1, 25 g, 157.69mmol, 1.0 equiv) was added in portions. The reaction mixture was stirredat 0° C. for 2 h. It was poured over ice, stirred and extracted withethyl acetate three times. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexaneas eluant) to afford Int-1.2. MS (ES): m/z 220.13 [M+H]⁺.

Synthesis of compound Int-1.3. A solution of compound Int-1.2 (20 g,91.05 mmol, 1.0 equiv) in THF (200 mL) was degassed by bubbling argonthrough for 10 min.2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (4.17 g, 4.55mmol, 0.05 equiv) were added under argon atmosphere and again degassedfor 5 min. To the mixture was added a solution of lithiumbis(trimethylsilyl)amide (1 M in THF, 182 mL, 182.1 mmol, 2.0 equiv) andit was stirred at 60° C. for 1 h. The reaction mixture was cooled toroom temperature, poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 3% methanol in dichloromethane as eluant) toafford Int-1.3. MS (ES): m/z 201.2 [M+H]⁺.

Synthesis of compound Int-1.4. To a solution of compound Int-1.3 (11.2g, 55.93 mmol, 1.0 equiv) in dichloromethane (110 mL) and pyridine (6.3mL, 78.30 mmol, 1.4 equiv) was added slowly acetic anhydride (6.34 mL,67.11 mmol, 1.2 equiv) at room temperature and stirred for 1 h. Thereaction mixture was poured over ice, stirred and extracted withdichloromethane three times. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 1% methanol indichloromethane as eluant) to afford Int-1.4. MS (ES): m/z 243.21[M+H]⁺.

Synthesis of compound Int-1. A round bottom flask charged with compoundInt-1.4 (6.1 g, 25.18 mmol, 1.0 equiv), 10% palladium on carbon (2 g)and methanol (60 mL) was vacuumed and purged with hydrogen three times.The reaction mixture was stirred under 1 atm of hydrogen at rt for 1 h.The flask was vacuumed and purged with nitrogen before it was opened toair. The reaction mixture was filtered through a pad of Celite® andrinsed with methanol. The filtrate was concentrated under reducedpressure and the residue was purified by flash column chromatography onsilica gel (CombiFlash®, 5% methanol in dichloromethane as eluant) toafford Int-1. MS (ES): m/z 153.2 [M+H]⁺.

Preparation of Intermediate Int-2:N-(4-(4-amino-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

Synthesis of compound Int-2.2. To a solution of2,4-difluoro-1-nitrobenzene (Int-2.1, 1.0 g, 6.29 mmol, 1.0 equiv) inTHF (10 mL) was added a solution of methylamine (33% in ethanol, 1.18mL, 12.58 mmol, 2.0 equiv) dropwise at 0° C. The reaction mixture wasstirred at room temperature for 2 h. It was poured over ice and wasextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to afford Int-2.2. MS (ES): m/z171.2 [M+H]⁺.

Synthesis of compound Int-2.3. A mixture of Int-2.2 (0.170 g, 0.99 mmol,1.0 equiv), Int-1 (0.152 g, 0.99 mmol, 1.0 equiv) and potassiumcarbonate (0.273 g, 1.98 mmol, 2.0 equiv) in N-methyl-2-pyrrolidone (1.7mL) was stirred at 130° C. for 12 h under nitrogen. It was cooled toroom temperature, poured over ice and extracted with ethyl acetate threetimes. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluant) toafford Int-2.3. MS (ES): m/z 303.3 [M+H]⁺.

Synthesis of compound Int-2. A round bottom flask charged with Int-2.3(0.180 g, 0.59 mmol, 1.0 equiv), 10% palladium on carbon (0.1 g) andmethanol (2 mL) was vacuumed and purged with hydrogen. The reactionmixture was stirred under 1 atm hydrogen at rt for 2 h. The flask wasvacuumed and purged with nitrogen before it was opened to air. Themixture was filtered through a pad of Celite® and rinsed with methanol.The filtrate was concentrated under reduced pressure and the residue waspurified by flash column chromatography on silica gel (CombiFlash®, 5%methanol in dichloromethane as eluant) to afford Int-2. MS (ES): m/z273.3 [M+H]⁺.

Preparation of Intermediate Int-3:N-(4-(4-amino-2-methyl-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

Synthesis of compound Int-3.2. Int-3.2 was prepared from1,3-difluoro-2-methyl-4-nitrobenzene (Int-3.1) following the proceduredescribed in the synthesis of compound Int-2.2. MS (ES): m/z 185.2[M+H]⁺.

Synthesis of compound Int-3.3. Int-3.3 was prepared from Int-3.2following the procedure described in the synthesis of compound Int-2.3.The product was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES): m/z317.03 [M+H]⁺.

Synthesis of compound Int-3. Int-3 was prepared from Int-3.3 followingthe procedure described in the synthesis of compound Int-2. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5% methanol in dichloromethane as eluant). MS (ES): m/z 287.3 [M+H]⁺.

Preparation of Intermediate Int-4:N-(4-(4-amino-2-cyano-3-(methylamino)phenoxy)pyridin-2-yl)acetamide

Synthesis of compound Int-4.2: To a solution of 2,6-difluorobenzonitrile(Int-4.1, 5.0 g, 35.94 mmol, 1.0 equiv) in concentrated sulfuric acid(15 mL) was slowly added concentrated nitric acid (6 mL) at −10° C. Thereaction mixture was stirred at room temperature for 15 min. It waspoured over crushed ice. The precipitates were collected by filtration,rinsed with a small amount of water and air-dried to afford Int-4.2. MS(ES): m/z 185.1 [M+H]⁺.

Synthesis of compound Int-4.3. To a solution of Int-4.2 (2.6 g, 14.12mmol, 1.0 equiv) in THF (25 mL) was added methylamine solution (40% inwater, 2.19 mL, 28.24 mmol, 2.0 equiv) dropwise at 0° C. The reactionmixture was stirred at room temperature for 2 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 6% ethyl acetatein hexane as eluant) to afford Int-4.3. MS (ES): m/z 196.2 [M+H]⁺.

Synthesis of compound Int-4.4. Int-4.4 was prepared from Int-4.3following the procedure described in the synthesis of compound Int-2.3.The residue was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES): m/z328.3 [M+H]⁺.

Synthesis of compound Int-4. A mixture of compound Int-4.4 (0.860 g,2.63 mmol, 1.0 equiv), ammonium chloride (1.406 g, 26.3 mmol, 10 equiv),iron powder (1.472, 26.3 mmol, 10 equiv) in ethanol (9 mL) and water (3mL) was stirred at 80° C. for 3 h under nitrogen. It was filteredthrough a pad of Celite®. The filtrate was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.5% methanol indichloromethane as eluant) to afford Int-4. MS (ES): m/z 298.3 [M+H]⁺.

Preparation of Intermediate Int-5:N-(4-((5-amino-6-(methylamino)pyridin-2-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound Int-5.2. To a solution of2,6-dichloro-3-nitropyridine (Int-5.1, 5.0 g, 25.91 mmol, 1.0 equiv) inethanol (30 mL) was added methylamine solution (33% in ethanol, 4.9 mL,51.82 mmol, 2.0 equiv) dropwise at 0° C. followed by sodium carbonate(4.10 g, 38.7 mmol, 1.5 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain Int-5.2. MS (ES): m/z 188.5 [M+H]⁺.

Synthesis of compound Int-5.3. A mixture of Int-5.2 (0.500 g, 2.67 mmol,1.0 equiv), Int-1 (0.405 g, 2.67 mmol, 1.0 equiv) and sodium carbonate(0.311 g, 2.93 mmol, 1.1 equiv) in DMF (5 mL) was stirred at 90° C. for12 h under nitrogen. It was cooled to room temperature, poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 25% ethylacetate in hexane as eluant) to afford 1.3. MS (ES): m/z 304.3 [M+H]⁺.

Synthesis of compound Int-5. Int-5 was prepared from Int-5.3 followingthe procedure described in the synthesis of compound Int-2. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5% methanol in dichloromethane as eluant). MS (ES): m/z 274.3 [M+H]⁺.

Preparation of Compounds Example 1:N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 1.2. To a solution of 1.1 (0.8 g, 5.71 mmol, 1.0equiv) and triethylamine (2.38 mL, 17.13 mmol, 3.0 equiv) in THF (8 mL)was added thiophosgene (0.52 mL, 6.85 mmol, 1.2 equiv) dropwise at 0° C.The reaction mixture was stirred at 0° C. for 30 min. It was poured intoice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 10% ethylacetate in hexane as eluant) to afford 1.2. MS (ES): m/z 183.2 [M+H]⁺.

Synthesis of compound I-1. To a solution of Int-2 (0.100 g, 0.37 mmol,1.0 equiv) and 1.2 (0.087 g, 0.47 mmol, 1.3 equiv) in THF (2 mL) wasadded N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.141 g, 0.74 mmol, 2.0 equiv). The reaction mixture was stirred at 50°C. for 4 h. It was cooled to room temperature, poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 4% methanol indichloromethane as eluant) to afford I-1. MS (ES): m/z: 421.6 [M+H]⁺; ¹HNMR (DMSO-d6, 400 M Hz): δ 10.14 (bs, 2H), 8.15-8.14 (d, J=5.6 Hz, 1H),7.65 (s, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 6.86-6.84 (d,J=8.0 Hz, 1H), 6.63-6.62 (d, J=3.6 Hz, 1H), 3.56 (s, 3H), 2.06 (s, 3H),1.34 (s, 9H).

Example 2:N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-2. To a solution of Int-3 (0.150 g, 0.52 mmol, 1.0 equiv)and 1.2 (0.124 g, 0.68 mmol, 1.3 equiv) in THF (3 mL) was addedN,N′-diisopropylcarbodiimide (0.087 mL, 1.04 mmol, 2.0 equiv). Thereaction mixture was stirred at 70° C. for 5 h. It was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 8% methanol in dichloromethane as eluant) to afford I-2.MS (ES): m/z: 435.1[M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H),10.10 (s, 1H), 8.14-8.13 (d, J=5.2 Hz, 1H), 7.58 (s, 1H), 7.31-7.29 (d,J=8.4 Hz, 1H), 6.84-6.80 (t, 1H), 6.73 (bs, 1H), 6.55 (bs, 1H), 3.77 (s,3H), 2.39 (s, 3H), 2.02 (s, 3H), 1.30 (s, 9H).

Example 3:N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-3. Compound I-3 was prepared from Int-4 and 1.2following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 5% methanol in dichloromethane as eluant). MS (ES): m/z:446.45 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz): δ 10.24 (s, 1H), 8.22-8.21 (d,J=5.6 Hz, 1H), 7.70 (bs, 2H), 7.01 (s, 1H), 6.69 (bs, 2H), 3.95 (bs,3H), 3.78 (bs, 1H), 2.07-2.06 (d, 3H), 1.27 (s, 9H).

Example 4:N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 4.2. Compound 4.2 was prepared from4-chloro-3-(trifluoromethyl)aniline (4.1) following the proceduredescribed in the synthesis of compound 1.2. The product was purified byflash column chromatography on silica gel (CombiFlash®, 8% ethyl acetatein hexane as eluant). MS (ES): m/z 238.5 [M+H]⁺.

Synthesis of I-4. Compound I-4 was prepared from 4.2 and Int-2 followingthe procedure described in the synthesis of compound I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5% methanol in dichloromethane as eluant). MS (ES): m/z: 476.6 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.49 (s, 1H), 8.41 (s, 1H),8.33-8.31 (d, J=8.8 Hz, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.70-7.65 (m,2H), 7.49-7.47 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 6.90-6.88 (d, J=8.4 Hz,1H), 6.63-6.61 (t, J=3.6 Hz, 1H), 3.77 (s, 3H), 2.03 (s, 3H).

Example 5:N-(4-((2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-5. Compound I-5 was prepared from Int-3 and 4.2following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 4% methanol in dichloromethane as eluant). MS (ES): m/z:490.71 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.43 (s, 1H),8.35 (s, 1H), 8.26-8.24 (d, J=8.4 Hz, 1H), 8.14-8.13 (d, J=5.6 Hz, 1H),7.68-7.66 (d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.34-7.32 (d, J=8.4 Hz, 1H),6.85-6.83 (d, J=7.6 Hz, 1H), 6.55-6.54 (d, J=4 Hz, 1H), 3.97 (s, 3H),2.50 (s, 3H), 2.02 (s, 3H).

Example 6:N-(4-((2-((2,4-difluorophenyl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 6.2. Compound 6.2 was prepared from2,4-difluoroaniline (6.1) following the procedure described in thesynthesis of compound 1.2. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexaneas eluant). MS (ES): m/z 172.2 [M+H]⁺.

Synthesis of compound I-6. Compound I-6 was prepared from Int-3 and 6.2following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2% methanol in dichloromethane as eluant). MS (ES): m/z:424.0 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H), 8.68 (s, 1H),8.18-8.16 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 7.37 (bs, 1H),7.23 (s, 1H), 7.14 (s, 1H), 6.84-6.82 (d, J=7.6 Hz, 1H), 6.57 (bs, 1H),3.94 (s, 3H), 2.46 (s, 3H), 2.07 (s, 3H).

Example 7:N-(4-((2-((3-(3-methoxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 7.2. A mixture of3-bromo-5-(trifluoromethyl)aniline (7.1, 0.7 g, 2.92 mmol, 1.0 equiv),3-methoxyazetidine hydrochloride (0.72 g, 5.83 mmol, 2.0 equiv), cesiumcarbonate (2.37 g, 7.3 mmol, 2.5 equiv) in 1,4-dioxane (20 mL) wasdegassed by bubbling through argon for 10 min. BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) (0.363 g, 0.584 mmol, 0.2equiv) and Pd₂(dba)₃ (0.267 g, 0.292 mmol, 0.1 equiv) was added, anddegassed for 5 min. The reaction mixture was stirred at 110° C. underargon for 5 h. It was cooled to room temperature, filtered through a padof Celite®. The filtrate was poured over water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 10-15% ethyl acetate in hexane as eluant) toafford 7.2. MS (ES): m/z 247.2 [M+H]⁺.

Synthesis of compound 7.3. Compound 7.3 was prepared from 7.2 followingthe procedure described in the synthesis of compound 1.2. MS (ES): m/z289.3 [M+H]⁺.

Synthesis of I-7. Compound I-7 was prepared from 7.3 and Int-2 followingthe procedure described in the synthesis of compound I-2. The productwas purified by trituration with methanol and dried under vacuum. MS(ES): m/z: 527.49 [M−H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H),9.16 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.68 (s, 1H), 7.65 (s, 1H),7.46-7.44 (d, J=8.4 Hz, 1H), 7.26-7.22 (m, 2H), 6.87-6.85 (d, J=8.0 Hz,1H), 6.62-6.61 (t, 1H), 6.30 (s, 1H), 4.36 (bs, 1H), 4.15-4.11 (t, 2H),3.69 (s, 5H), 3.27 (s, 3H), 1.99 (s, 3H).

Example 8:N-(4-((2-((4-(2-cyanopropan-2-yl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 8.2. Compound 8.2 was prepared from2-(4-aminophenyl)-2-methylpropanenitrile (8.1) following the proceduredescribed in the synthesis of compound 1.2. The product was purified byflash column chromatography on silica gel (CombiFlash®, 8% ethyl acetatein hexane as eluant). MS (ES): m/z 203.2 [M+H]⁺.

Synthesis of I-8. Compound I-8 was prepared from 8.2 and Int-2 followingthe procedure described in the synthesis of compound I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,10% methanol in dichloromethane as eluant). MS (ES): m/z: 441.29[M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.12 (s, 1H), 8.15-8.14 (d,J=5.2 Hz, 1H), 7.67 (s, 1H), 7.91-7.89 (d, J=8 Hz, 1H), 7.65 (s, 1H),7.49-7.47 (m, 2H), 7.43-7.41 (d, J=8 Hz, 1H), 7.24 (s, 1H), 6.87-6.85(d, J=8 Hz, 1H), 6.62 (bs, 1H), 3.70 (s, 3H), 2.03 (s, 3H), 1.69 (s,6H).

Example 9:N-(4-((1-methyl-2-((4-(1-methyl-1H-imidazol-5-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 9.3. To a solution of 5-iodo-1-methyl-1H-imidazole(9.2, 1.9 g, 9.13 mmol, 1.0 equiv) in THF (20 mL) was added n-butyllithium dropwise (2.5 M in hexane, 7.3 mL, 18.26 mmol, 2.0 equiv) at−78° C. over 5 min. To the reaction mixture was added a solution of4-nitro-2-(trifluoromethyl)benzaldehyde (9.1, 2.00 g, 9.13 mmol, 1.0equiv) in THF (5 mL) and stirred at −78° C. for 10 min. It was pouredover saturated ammonium chloride solution, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4% methanol in dichloromethane as eluant) toafford 9.3. MS (ES): m/z 302.2 [M+H]⁺.

Synthesis of compound 9.4. To a solution of compound 9.3 (0.460 g, 1.53mmol, 1.0 equiv) in THF (10 mL) was added phosphorus tribromide (0.44mL, 4.59 mmol, 3.0 equiv) and the reaction mixture was stirred at 80° C.for 2 h. It poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 1% methanol in dichloromethane as eluant) to afford 9.4.MS (ES): m/z 286.2 [M+H]⁺.

Synthesis of compound 9.5. A mixture of compound 9.4 (0.210 g, 0.736mmol, 1.0 equiv) and 10% palladium on carbon (0.1 g) in in methanol (10mL) was stirred at rt under 1 atm of hydrogen for 2 h. It was filteredthrough a pad of Celite® and rinsed with methanol. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel (CombiFlash®, 3% methanol indichloromethane as eluant) to afford 9.5. MS (ES): m/z 256.3 [M+H]⁺.

Synthesis of compound 9.6. Compound 9.6 was prepared from 9.4 followingthe procedure described in the synthesis of compound 1.2. MS (ES): m/z298.3 [M+H]⁺.

Synthesis of I-9. Compound I-9 was prepared from 9.6 and Int-2 followingthe procedure described in the synthesis of compound I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,3.5% methanol in dichloromethane as eluant). MS (ES): m/z: 534.15[M−H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.32 (s, 1H), 8.32(s, 1H), 8.15-8.08 (m, 2H), 7.65 (s, 1H), 7.46-7.42 (d, J=8.4 Hz, 1H),7.26 (s, 1H), 7.12 (s, 1H), 7.01-6.99 (m, 1H), 6.87-6.82 (m, 2H),6.62-6.61 (m, 1H), 4.14 (s, 2H), 3.70 (s, 3H), 3.51 (s, 3H), 1.99 (s,3H).

Example 10:N-(4-((2-((4-((1H-pyrazol-4-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 10.2. To a solution of 4-iodo-1H-pyrazole (10.1,5.0 g, 25.78 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride(1.48 g, 30.93 mmol, 1.2 equiv) in small portions at 0° C. After theaddition, the mixture was stirred for 15 min followed by the addition of4-methoxybenzyl chloride (4.85 g, 30.93 mmol, 1.2 equiv) and stirred atroom temperature for 2 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 6% ethyl acetate inhexane as eluant) to afford 10.2. MS (ES): m/z 315.13 [M+H]⁺.

Synthesis of compound 10.4. To a solution of 10.2 (2.06 g, 6.37 mmol,1.0 equiv) in THF (20 mL) was added a solution of isopropyl magnesiumchloride lithium chloride complex (1.3 M in THF, 12.25 mL, 15.92 mmol,2.5 equiv) at −10° C. The reaction mixture was stirred for 30 min at−10° C. and was added a solution of4-nitro-2-(trifluoromethyl)benzaldehyde (10.3, 1.12 g, 5.09 mmol, 0.8equiv) in THF (10 mL) and stirred for 5 min. It was poured over ice,stirred and acidified with 1 N hydrochloric acid and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 25% ethyl acetate in hexane as eluant) toafford 10.4. MS (ES): m/z 408.4 [M+H]⁺.

Synthesis of compound 10.5. To a solution of 10.4 (0.700 g, 1.72 mmol,1.0 equiv) in dichloromethane (10 mL) and added trifluoroacetic acid (7mL) was added triethylsilane (3.5 mL) at 0° C. It was allowed to warm to50° C. and stirred for 1 h. It was carefully poured over cold saturatedsodium bicarbonate solution, stirred and extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 15% ethyl acetate in hexane as eluant) to afford 10.5. MS(ES): m/z 392.4 [M+H]⁺.

Synthesis of compound 10.6. Compound 10.6 was prepared from 10.5following the procedure described in the synthesis of compound 9.5. MS(ES): m/z 362.4 [M+H]⁺.

Synthesis of compound 10.7. Compound 10.7 was prepared from 10.6following the procedure described in the synthesis of compound 1.2. MS(ES): m/z 404.4 [M+H]⁺.

Synthesis of compound 10.8. Compound 10.8 was prepared from 10.7 andInt-2 following the procedure described in the synthesis of compoundI-1. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.6% methanol in dichloromethane as eluant). MS (ES):m/z 626.6 [M+H]⁺.

Synthesis of I-10. A mixture of 10.8 (0.162 g, 0.258 mmol, 1.0 equiv)and palladium hydroxide (0.200 g) in ethanol (8 mL) and cyclohexene (4mL) was stirred at 80° C. for 16 h. The reaction mixture was filteredthrough a pad of Celite® and rinsed with ethanol. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel (CombiFlash®, 3.5% methanol indichloromethane as eluant) to afford I-10. MS (ES): m/z: 522.7 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.28 (s, 1H), 8.24 (s, 1H),8.15-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.45-7.39 (m, 4H), 7.26 (s,1H), 7.06 (bs, 2H), 6.87-6.81 (m, 1H), 6.62-6.61 (d, J=3.6 Hz, 1H), 3.90(bs, 2H), 3.70 (s, 3H), 2.02 (s, 3H).

Example 11:N-(4-((2-((3-methoxy-4-(methoxymethyl)-5-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 11.2. To a solution of4-nitro-2-(trifluoromethyl)benzoic acid (11.1, 10 g, 42.53 mmol, 1.0equiv) in THF (200 mL) was added sodium borohydride (4.84 g, 127.59mmol, 3.0 equiv) in portions at 0° C. followed by the addition of borontrifluoride etherate (15.7 mL, 127.59 mmol, 3.0 equiv) slowly over aperiod of 30 min. The reaction mixture was stirred at room temperaturefor 16 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 9% ethyl acetate in hexane as eluant) to afford11.2. MS (ES): m/z 222.1 [M+H]⁺.

Synthesis of compound 11.3. To a solution of 11.2 (9.0 g, 40.7 mmol, 1.0equiv) in dichloromethane (90 mL) was added silver oxide (47 g, 203.5mmol, 5.0 equiv), water (9 mL) followed by methyl iodide (25 mL, 407mmol, 10 equiv). The reaction mixture was stirred at room temperaturefor 16 h in dark. It was filtered through a pad of Celite® and thefiltrate was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4% ethyl acetate in hexane as eluant) to afford11.3. MS (ES): m/z 236.2 [M+H]⁺.

Synthesis of compound 11.4. To a solution of 11.3 (4.6 g, 19.56 mmol,1.0 equiv) in sulfuric acid (46 mL) was added1,3-dibromo-5,5-dimethylhydantoin (5.59 g, 19.56 mmol, 1.0 equiv). Thereaction mixture was stirred at room temperature for 16 h. It was pouredover ice-water and stirred. The precipitates were collected byfiltration, rinsed with water and dried under vacuum. MS (ES): m/z 315.1[M+H]⁺.

Synthesis of compound 11.5. To a solution of 11.4 (1.5 g, 4.78 mmol, 1.0equiv) in 1,4-dioxane (12 mL) and water (12 mL) was added potassiumhydroxide (0.602 g, 10.75 mmol, 2.25 equiv). The reaction mixture wasdegassed by bubbling argon for 10 min.2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.052 g, 0.123mmol, 0.18 equiv) and tris(dibenzylideneacetone)dipalladium (O) (0.131g, 0.143 mmol, 0.03 equiv) were added, again degassed for 5 min. Thereaction mixture was stirred at 80° C. under argon for 1 h. It wascooled to room temperature, filtered through a pad of Celite®. Thefiltrate was poured over water, extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 9% ethyl acetate in hexane as eluant) to afford 11.5. MS(ES): m/z 252.2 [M+H]⁺.

Synthesis of compound 11.6. To a mixture of 11.5 (0.45 g, 1.79 mmol, 1.0equiv) and potassium carbonate (0.494 g, 3.58 mmol, 2.0 equiv) in DMF (4mL) was added methyl iodide (0.381 g, 2.68 mmol, 1.5 equiv). Thereaction mixture was stirred at 70° C. under argon for 1 h. It waspoured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5% ethyl acetate in hexane as eluant) to afford 11.6. MS(ES): m/z 266.2 [M+H]⁺.

Synthesis of compound 11.7. Compound 11.7 was prepared from 11.6following the procedure described in the synthesis of compound 9.5. MS(ES): m/z 236.3 [M+H]⁺.

Synthesis of compound 11.8. To a solution of 11.7 (0.120 g, 0.510 mmol,1.0 equiv) in dichloromethane (3 mL) was added solution of sodiumbicarbonate (0.214 g, 2.55 mmol, 5.0 equiv) in water (1 mL) followed bythiophosgene (0.146 g, 1.27 mmol, 2.5 equiv) at 0° C. The reactionmixture was stirred at room temperature for 1 h. It was poured overice-water and extracted with dichloromethane. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to obtain 11.8. MS(ES): m/z 278.3 [M+H]⁺.

Synthesis of I-11. Compound I-11 was prepared from 11.8 and Int-2following the procedure described in the synthesis of compound I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.7% methanol in dichloromethane as eluant). MS (ES): m/z:516.5 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.41 (s, 1H),8.16-8.15 (d, J=5.6 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.48-7.46 (d,J=8.4 Hz, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 6.89-6.81 (m, 1H), 6.63-6.62(d, J=3.6 Hz, 1H), 4.43 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 3.28 (s,3H), 2.02 (s, 3H).

Example 12:(R)—N-(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidin-3-yl)-5-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidin-3-yl)-5-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 12.2. To a mixture of3-(trifluoromethyl)benzaldehyde (12.1, 10 g, 57.43 mmol, 1.0 equiv) inconcentrated sulfuric acid (98%, 20 mL) at 0° C. was slowly added nitricacid (2.5 mL). The reaction mixture was stirred at 50° C. for 8 h. Itwas poured over crushed ice, stirred and extracted with ethyl acetate.The combined organic layers were washed with saturated sodiumbicarbonate, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 10% ethyl acetate inhexane as eluant) to afford 12.2. MS (ES): m/z 220.2 [M+H]⁺.

Synthesis of compound 12.3. To a solution ofethyldiethylphosphinoacetate (4.74 g, 22.59 mmol, 1.1 equiv) in THF (50mL) was added sodium hydride (1.18 g, 24.64 mmol, 1.2 equiv) at 0° C.and stirred for 30 min. To the solution was added 12.2 (4.5 g, 20.54mmol, 1.2 equiv) and the mixture was stirred at room temperature for 3h. It was poured into ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20% ethyl acetate in hexane as eluant) toafford 12.3. MS (ES): m/z 290.2 [M+H]⁺.

Synthesis of compound (±)-12.4. A solution of compound 12.3 (4.0 g,13.83 mmol, 1.0 equiv) and tetramethylguanidine (0.6 mL) in nitromethane(40 mL) was stirred at 80° C. for 2 h. It was poured into ice-water,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 12% ethylacetate in hexane as eluant) to afford (±)-12.4. MS (ES): m/z 351.3[M+H]⁺.

Synthesis of compound (±)-12.5. To a solution of (±)-12.4 (1.1 g, 3.14mmol, 1.0 equiv) in isopropyl alcohol (60 mL) and 1 N aqueoushydrochloric acid (30 mL) was added zinc dust (3.9 g, 61.23 mmol, 19.5equiv) in portions at 0° C. After the addition, the reaction mixture wasallowed to warm to rt and stirred for 2 h. It was slowly poured into astirring saturated aqueous solution of sodium bicarbonate, and themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 10% methanol indichloromethane as eluant) to afford the amine, which was dissolved inethanol (20 mL), added triethylamine (2 mL) and heated to reflux for 16h. The reaction mixture was poured into ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 4.1% methanol indichloromethane as eluant) to afford (±)-12.5. MS (ES): m/z 245.2[M+H]⁺.

Synthesis of compound (±)-12.6. To a solution of 12.5 (0.4 g, 1.64 mmol,1.0 equiv) in acetic acid (5 mL) was added phthalic anhydride (0.485 g,3.28 mmol, 2.0 equiv) and stirred at 80° C. for 4 h. It was poured intoice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,10% methanol in dichloromethane as eluant) to afford (±)-12.6. MS (ES):m/z 375.3 [M+H]⁺.

Synthesis of compound (±)-12.7. A mixture of (±)-12.6 (0.271 g, 0.723mmol, 1.0 equiv) and potassium carbonate (0.209 g, 1.51 mmol, 2.1 equiv)in DMF (3 mL) was stirred for 15 min and was added methyl iodide (0.123g, 0.867 mmol, 1.2 equiv). The reaction mixture was stirred at 85° C.for 3 h. It was poured into ice-water and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4.7% methanol in dichloromethane as eluant) to afford(±)-12.7. MS (ES): m/z 389.4 [M+H]⁺.

Synthesis of compound (±)-12.8. To a solution of (±)-12.7 (0.190 g,0.489 mmol, 1.0 equiv) in methanol (10 mL) was added hydrazine (99%, 1mL) and the mixture was heated to reflux for 2 h. It was poured intoice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain (±)-12.8. MS (ES): m/z259.2 [M+H]⁺.

Synthesis of compound (±)-12.9. Compound (±)-12.9 was prepared fromcompound (±)-12.8 following the procedure described in the synthesis of11.8. MS (ES): m/z 301.3 [M+H]⁺.

Synthesis of compound (±)-I-12. Compound (±)-I-12 was prepared from(±)-12.9 and Int-2 following the procedure described in the synthesis ofcompound I-1. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4.8% methanol in dichloromethane as eluant). MS(ES): m/z 539.5 [M+H]⁺.

I-12-a and I-12-b. Enantiomers of (±)-I-12 were separated on HPLC(CHIRALPAK IH (250 mm×21 mm, 5 μm); mobile phase: (A) 0.1%diethylamine/n-hexane (B) 0.1% diethylamine/isopropanol:acetonitrile(70:30); flow rate: 20 mL/min) to get first eluting fraction (I-12-a)and second eluting fraction (I-12-b). (*Absolute stereochemistry notdetermined.) I-12-a: MS (ES): m/z: 539.8 [M+H]⁺; ¹H NMR (DMSO-d6, 400MHz): δ 10.50 (s, 1H), 9.37 (s, 1H), 8.34 (s, 1H), 8.16-8.14 (d, J=5.6Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 7.48-7.46 (d, J=8.4 Hz, 1H), 7.29(s, 1H), 7.25 (s, 1H), 6.89-6.87 (m, 1H), 6.63-6.62 (m, 1H), 3.82-3.80(m, 1H), 3.72 (s, 3H), 3.69-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.81 (s,3H), 2.79-2.72 (m, 1H), 2.42-2.33 (m, 1H), 2.02 (s, 3H).

I-12-b: MS (ES): m/z: 539.4 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 9.37 (s, 1H), 8.34 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 8.01(s, 1H), 7.65 (s, 1H), 7.48-7.46 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.25(s, 1H), 6.89-6.86 (m, 1H), 6.63-6.61 (m, 1H), 3.82-3.80 (m, 1H), 3.72(s, 3H), 3.69-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.81 (s, 3H), 2.79-2.72(m, 1H), 2.42-2.33 (m, 1H), 2.02 (s, 3H).

Example 13:N-(4-((1-methyl-2-((6-morpholinopyridin-2-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 13.2. A mixture of 6-bromopyridin-2-amine (13.1,1.5 g, 8.67 mmol, 1.0 equiv) and morpholine (7.47 mL, 86.7 mmol, 10equiv) was stirred in a microwave reactor at 150° C. for 4 h. It wascooled to room temperature, poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane as eluant) toafford 13.2. MS (ES): m/z 180.3 [M+H]⁺.

Synthesis of compound 13.3. Compound 13.3 was prepared from 13.2following the procedure described in the synthesis of compound 1.2. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 15% ethyl acetate in hexane as eluant). MS (ES): m/z 222.3[M+H]⁺.

Synthesis of I-13. Compound I-12 was prepared from 13.3 and Int-2following the procedure described in the synthesis of compound I-1. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 8% methanol in dichloromethane as eluant). MS (ES): m/z:460.45 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.13 (s, 1H),8.15-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.57-7.46 (m, 3H), 7.29 (s,1H), 6.90-6.88 (d, J=8.4 Hz, 1H), 6.63-6.62 (d, J=3.6 Hz, 1H), 6.40-6.38(d, J=8 Hz, 1H), 3.69 (bs, 8H), 3.55 (s, 3H), 2.02 (s, 3H).

Example 14:N-(4-((2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 14.2. To a solution of benzyl alcohol (17.05 g,157.69 mmol, 1.0 equiv) in THF (250 mL) was added sodium hydride (12.61g, 315.38 mmol, 2 equiv) at 0° C. and stirred for 1 h.2-Chloro-4-nitropyridine (14.1, 25 g, 157.69 mmol, 1.0 equiv) was addedand the reaction mixture was stirred at 0° C. for 2 h. It was pouredover ice, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 10%ethyl acetate in hexane as eluant) to afford 1.1. MS (ES): m/z 220.13[M+H]⁺.

Synthesis of compound 14.3. A solution of 14.2 (20 g, 91.05 mmol, 1.0equiv) in THF (200 mL) was degassed by bubbling argon for 10 min.2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (4.34 g, 9.105mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (0) (4.17 g,4.55 mmol, 0.05 equiv) were added, and degassed for 5 min. To themixture was added a solution of lithium bis(trimethylsilyl)amide (1 M inTHF, 182 mL, 182.1 mmol, 2.0 equiv) and the reaction mixture was stirredat 60° C. under argon for 1 h. It was cooled to room temperature, pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 3%methanol in dichloromethane as eluant) to afford 14.3. MS (ES): m/z201.2 [M+H]⁺.

Synthesis of compound 14.4. To a solution of 14.3 (0.8 g, 4.0 mmol, 1.0equiv) in dichloromethane (10 mL) was added triethylamine (1.67 mL, 12.0mmol, 3.0 equiv) followed by cyclopropyl carbonyl chloride (0.49 g, 4.8mmol, 1.2 equiv) at room temperature and stirred for 1 h. It was pouredover ice, stirred and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.2% methanol in dichloromethane as eluant) to afford 14.4. MS (ES): m/z269.3 [M+H]⁺.

Synthesis of compound 14.5. Compound 14.5 was prepared from 14.4following the procedure described in the synthesis of Int-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5% methanol in dichloromethane as eluant). MS (ES): m/z 179.2 [M+H]⁺.

Synthesis of compound 14.7. To a solution of4-amino-2-(trifluoromethyl)benzoic acid (14.6, 10 g, 48.75 mmol, 1.0equiv) in DMF (30 mL) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(18.4 g, 58.5 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirredfor 30 min and was added 1-ethylpiperazine (6.67, 58.5 mmol, 1.2 equiv)followed by N,N-diisopropylethylamine (24 mL, 146.25 mmol, 3.0 equiv).It was stirred at room temperature for 3 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.5% methanol in dichloromethane as eluant) to afford 14.7. MS (ES): m/z302.3 [M+H]⁺.

Synthesis of compound 14.8. To a solution of 14.7 (2 g, 6.64 mmol, 1.0equiv) in THF (20 mL) was added a solution of lithium aluminum hydride(1 M in THF, 19.9 mL, 19.92 mmol, 3.0 equiv) at 0° C. The reactionmixture was heated to reflux for 3 h. It was cooled to room temperature,carefully poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain 14.8. MS (ES): m/z 288.3 [M+H]⁺.

Synthesis of compound 14.9. Compound 14.9 was prepared from 14.8following the procedure described in the synthesis of compound 1.2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.0% methanol in dichloromethane as eluant). MS (ES): m/z330.3 [M+H]⁺.

Synthesis of compound 14.11. To a solution of2,4-difluoro-1-nitrobenzene (14.10, 1.0 g, 6.29 mmol, 1.0 equiv) in THF(10 mL) was added methylamine solution (33% in ethanol, 1.18 mL, 12.58mmol, 2.0 equiv) dropwise at 0° C. The reaction mixture was stirred atroom temperature for 2 h. It was poured over ice-water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 14.11. MS (ES): m/z 171.2 [M+H]⁺.

Synthesis of compound 14.12. Compound 14.12 was prepared from 14.11 and14.5 following the procedure described in the synthesis of compoundInt-2.3. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS(ES): m/z 329.3 [M+H]⁺.

Synthesis of compound 14.13. Compound 14.13 was prepared from 14.12following the procedure described in the synthesis of compound Int-2.The product was purified by flash column chromatography on silica gel(CombiFlash®, 5% methanol in dichloromethane as eluant). MS (ES): m/z299.3 [M+H]⁺.

Synthesis of I-14. Compound I-14 was prepared from 14.9 and 14.13following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 10% methanol in dichloromethane as eluant). MS (ES): m/z:594.30 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.79 (s, 1H), 9.31 (s, 1H),8.24 (s, 1H), 8.19-8.15 (m, 2H), 7.68-7.66 (d, J=8.4 Hz, 1H), 7.62 (s,1H), 7.45-7.43 (d, J=7.6 Hz, 1H), 7.26 (s, 1H), 6.87-6.85 (d, J=10.4 Hz,1H), 6.66-6.65 (d, J=3.2 Hz, 1H), 3.70 (s, 3H), 3.55 (s, 2H), 2.33 (bs,10H), 1.95 (bs, 1H), 1.01-0.97 (t, 3H), 0.75 (bs, 4H).

Example 15:4-((2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpicolinamide

Synthesis of compound 15.2. A mixture of compound 15.1 (0.5 g, 2.93mmol, 1.0 equiv) and 1 M hydrochloric acid (5 mL) was stirred at 150° C.in a microwave reactor for 2 h. It was poured over saturated sodiumbicarbonate solution and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,3% methanol in dichloromethane as eluant) to afford 15.2. MS (ES): m/z153.2 [M+H]⁺.

Synthesis of compound 15.3. Compound 15.3 was prepared from Int-2.2 and15.2 following the procedure described in the synthesis of compoundInt-2.3. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 2.0% methanol in dichloromethane as eluant). MS(ES): m/z 303.3 [M+H]⁺.

Synthesis of compound 15.4. Compound 15.4 was prepared from 15.3following the procedure described in the synthesis of compound Int-2.The product was purified by flash column chromatography on silica gel(CombiFlash®, 5% methanol in dichloromethane as eluant). MS (ES): m/z273.3 [M+H]⁺.

Synthesis of I-15. Compound I-15 was prepared from 15.4 and 14.9following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 10% methanol in dichloromethane as eluant). MS (ES): m/z:568.9 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 9.35 (s, 1H), 8.80-8.78 (d,J=4.8 Hz, 1H), 8.50-8.49 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.21-8.19 (d,J=8.0 Hz, 1H), 7.69-7.67 (d, J=8.4 Hz, 1H), 7.50-7.48 (d, J=8.4 Hz, 1H),7.37-7.36 (d, J=2.4 Hz, 1H), 7.33 (s, 1H), 7.17-7.15 (m, 1H), 6.93-6.90(t, J=8.4 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 2.76 (s, 3H), 2.42 (bs,6H), 2.33 (bs, 4H), 1.01-0.97 (t, 3H).

Example 16: 4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpicolinamide

Synthesis of I-16. Compound I-16 was prepared from compound 15.4 andcompound 1.2 following the procedure described in the synthesis ofcompound I-2. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 3% methanol in dichloromethane as eluant). MS(ES): m/z: 421.46 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 8.49-8.48 (d,2H), 7.46 (bs, 2H), 7.17-7.11 (m, 2H), 6.89-6.87 (d, J=7.2 Hz, 1H), 3.56(bs, 3H), 2.84 (s, 3H), 1.35 (s, 9H).

Example 17:N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)lacetamide

Synthesis of compound 17.2. Compound 17.2 was prepared from 17.1following the procedure described in the synthesis of compound 1.2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 12% ethyl acetate in hexane as eluant). MS (ES): m/z 196.3[M+H]⁺.

Synthesis of I-17. Compound I-17 was prepared from 17.2 and Int-2following the procedure described in the synthesis of compound I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3% methanol in dichloromethane as eluant). MS (ES): m/z:434.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.56-10.50 (m, 2H),8.18-8.16 (d, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.35-7.16 (m, 2H), 6.84-6.78(t, J=7.6 Hz, 1H), 6.64 (bs, 1H), 5.92 (s, 1H), 3.61 (bs, 3H), 3.42 (s,3H), 2.04 (s, 3H), 1.27 (s, 9H).

Example 18:N-(4-((2-((3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-18. Compound I-18 was prepared from 17.2 and Int-3following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3% methanol in dichloromethane as eluant). MS (ES): m/z:448.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.53-10.48 (t, 1H), 8.76 (s,1H), 8.15-8.12 (m, 1H), 7.58 (s, 1H), 7.07-7.05 (d, J=8.0 Hz, 1H),6.78-6.74 (t, 1H), 6.56-6.55 (d, J=5.6 Hz, 1H), 6.07 (s, 1H), 3.72 (s,3H), 3.61 (bs, 3H), 2.37 (s, 3H), 2.03 (s, 3H), 1.26 (s, 9H).

Example 19:(S)—N-(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 19.1. To a round-bottom flask equipped with aDean-Stark apparatus and a condenser was charged with5-(tert-butyl)-1H-pyrazol-3-amine (17.1, 5.0 g, 35.92 mmol, 1.0 equiv),2, 5-hexanedione (4.09 g, 35.92 mmol, 1.0 equiv), toluene (100 mL) and afew drops of acetic acid (catalytic). The reaction mixture was heated toreflux for 3 hours. It was cooled rt and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 12% ethyl acetate in hexane as eluant) toafford 19.1. MS (ES): m/z 218.3 [M+H]⁺.

Synthesis of compound 19.3 and 19.4. A mixture of 19.1 (2.5 g, 11.50mmol, 1.0 equiv), 19.2 (1.91 g, 11.50 mmol, 1.0 equiv) and cesiumcarbonate (7.49 g, 23 mmol, 2.0 equiv) in DMF (15 mL) was stirred at 70°C. for 12 h under nitrogen. It was poured into ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2% ethyl acetate inhexane as eluant) to afford 19.3. MS (ES): m/z 287.4 [M+H]⁺ and 19.4. MS(ES): m/z 248.3 [M+H]⁺.

Synthesis of compound 19.5 A solution of 19.3 (0.100 g, 0.347 mmol, 1.0equiv) and hydroxylamine hydrochloride (0.239 g, 3.47 mmol, 10 equiv) inethanol-water (2/1, v/v, 3 mL) was stirred at 120° C. by a microwavereactor for 1 h. It was poured into ice-water and pH was adjusted toabout 10 by the addition of 2 N aqueous sodium hydroxide solution. Themixture was extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford 19.5. MS (ES): m/z210.3 [M+H]⁺.

Synthesis of compound 19.6. Compound 19.6 was prepared from 19.5following the procedure described in the synthesis of compound 1.2. MS(ES): m/z 252.3 [M+H]⁺.

Synthesis of I-19. Compound I-19 was prepared from 19.6 and Int-2following the procedure described in the synthesis of compound I-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 1.4% methanol in dichloromethane as eluant). MS (ES): m/z:490.85 [M+H]⁺, ¹H NMR (CDCl₃, 400 M Hz): δ 8.14-8.12 (d, J=5.6 Hz, 1H),7.99 (bs, 1H), 7.82 (bs, 1H), 7.17-7.15 (d, J=7.6 Hz, 1H), 6.86-6.84 (d,J=8.0 Hz, 1H), 6.64 (bs, 1H), 5.27 (bs, 1H), 4.39 (bs, 1H), 4.25 (bs,1H), 4.14 (bs, 2H), 4.02 (bs, 1H), 3.49 (s, 3H), 2.54 (bs, 2H), 2.20 (s,3H), 1.35 (s, 9H).

Example 20:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 20.1. Compound 20.1 was prepared from compound19.4 following the procedure described in the synthesis of compound19.5. MS (ES): m/z 210.3 [M+H]⁺.

Synthesis of compound 20.2. Compound 20.2 was prepared from compound20.1 following the procedure described in the synthesis of 11.8. Thecrude product was used without further purification. MS (ES): m/z 252.3[M+H]⁺.

Synthesis of compound I-20. Compound I-20 was prepared from 20.2 andInt-2 following the procedure described in the synthesis of compoundI-1. The product was purified by flash column chromatography on silicagel (CombiFlash®, 1.5% methanol in dichloromethane as eluant). MS (ES):m/z: 490.25 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.51 (s,1H), 8.14-8.13 (d, J=6.0 Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d, J=8.0 Hz,1H), 7.16 (s, 1H), 7.08-7.06 (d, J=8 Hz, 1H), 6.81-6.79 (m, 1H),6.61-6.60 (d, J=3.6 Hz, 1H), 5.22 (bs, 1H), 4.08-4.07 (m, 2H), 3.99-3.95(m, 1H), 3.85-3.82 (m, 2H), 3.62 (s, 3H), 2.24 (bs, 1H), 2.02 (s, 3H),1.39 (s, 9H).

Example 21:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-21. Compound I-21 was prepared from 20.2 and Int-4following the procedure described in the synthesis of compound I-1. Theproduct was purified by preparative HPLC. MS (ES): m/z: 515.8 [M+H]⁺, ¹HNMR (DMSO-d6, 400 MHz): δ 10.60 (s, 1H), 9.88 (s, 1H), 8.22-8.20 (d,J=5.6 Hz, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.02-7.00 (d, J=8.4 Hz, 1H),6.70-6.68 (m, 1H), 6.51 (s, 1H), 5.25 (bs, 1H), 4.10-4.07 (m, 2H), 3.91(s, 3H), 3.87-3.81 (m, 2H), 2.37-2.34 (m, 1H), 2.24-2.20 (m, 1H), 2.04(s, 3H), 1.39 (s, 9H).

Example 22:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-22. Compound I-22 was prepared from 20.2 and Int-5following the procedure described in the synthesis of compound I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.2% methanol in dichloromethane as a eluant). MS (ES):m/z: 491.45 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 9.81 (s,1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.79-7.77 (d, J=8 Hz, 1H), 7.75 (s,1H), 6.84-6.82 (d, J=8 Hz, 1H), 6.71-6.70 (d, J=4 Hz, 1H), 6.56 (s, 1H),5.24 (bs, 1H), 4.08 (bs, 2H), 3.87-3.81 (m, 2H), 3.59 (s, 3H), 2.33 (bs,1H), 2.25-2.22 (m, 1H), 2.04 (s, 3H), 1.39 (s, 9H).

Example 23:(R)—N-(4-((2-((3-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 23.2 and 23.3. Compound 23.2 and 23.3 wereprepared from compound 19.1 and 23.1 following the procedure describedin the synthesis of compound 19.3 and 19.4. The isomers were separatedby flash column chromatography on silica gel (CombiFlash®, 2% ethylacetate in hexane as eluant) to afford 23.2. MS (ES): m/z 287.4 [M+H]⁺and 23.3. MS (ES): m/z 248.3 [M+H]⁺.

Synthesis of I-23. Compound I-23 was prepared from 23.2 following theprocedures described in each step in the synthesis of compound I-19. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 1.5% methanol in dichloromethane as eluant). MS (ES): m/z:490.80 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 1H), 10.51 (s,1H), 8.16-8.15 (d, J=5.2 Hz, 1H), 7.65 (bs, 1H), 7.17-7.15 (d, J=8.4 Hz,1H), 7.07 (s, 1H), 6.80-6.78 (d, J=8.0 Hz, 1H), 6.63 (bs, 1H), 5.21 (bs,1H), 4.01-3.99 (m, 2H), 3.83-3.77 (m, 2H), 3.65 (bs, 1H), 3.39 (s, 3H),2.22-2.20 (m, 2H), 2.03 (s, 3H), 1.26 (s, 9H).

Example 24:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-24. Compound I-24 was prepared from 23.3following the procedures described in each step in the synthesis ofcompound I-20. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluant).MS (ES): m/z: 490.37 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H),9.56 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d,J=8.4 Hz, 1H), 7.19 (s, 1H), 7.10-7.04 (d, J=8 Hz, 1H), 6.84-6.82 (m,1H), 6.62-6.61 (d, J=3.6 Hz, 1H), 5.24 (bs, 1H), 4.10-4.07 (m, 2H),4.01-3.96 (m, 1H), 3.89-3.83 (m, 2H), 3.63 (s, 3H), 2.24 (bs, 1H), 2.03(s, 3H), 1.39 (s, 9H).

Example 25:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-25. Compound I-25 was prepared from Int-4 and24.2 following the procedure described in the synthesis of compound I-1.The product was purified by flash column chromatography on silica gel(CombiFlash®, 1.8% methanol in dichloromethane as eluant). MS (ES): m/z:515.36 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.60 (s, 1H), 9.88 (s, 1H),8.22-8.20 (d, J=5.6 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.02-7.00 (d,J=8.4 Hz, 1H), 6.70-6.68 (m, 1H), 6.51 (s, 1H), 5.25 (bs, 1H), 4.10-4.07(m, 2H), 3.91 (s, 3H), 3.88-3.84 (m, 2H), 2.37-2.34 (m, 1H), 2.23-2.22(m, 1H), 2.04 (s, 3H), 1.39 (s, 9H).

Example 26:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-26. Compound I-26 was prepared from Int-5 and24.2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.1% methanol in dichloromethane as eluant). MS (ES): m/z:491.40 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 9.81 (s, 1H),8.19-8.18 (d, J=5.6 Hz, 1H), 7.79-7.77 (d, J=8 Hz, 1H), 7.75 (s, 1H),6.84-6.82 (d, J=8 Hz, 1H), 6.71-6.70 (d, J=4 Hz, 1H), 6.56 (s, 1H), 5.24(bs, 1H), 4.08 (bs, 2H), 3.85-3.81 (m, 2H), 3.59 (s, 3H), 2.33 (bs, 1H),2.25-2.20 (m, 1H), 2.04 (s, 3H), 1.39 (s, 9H).

Example 27:N-(4-((2-((5-(tert-butyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 27.2. To a solution of tetrahydro-2H-pyran-4-ol(27.1, 4.0 g, 39.16 mmol, 1.0 equiv) in dichloromethane (40 mL) andtriethylamine (13.64 mL, 97.9 mmol, 2.5 equiv) at 0° C. was addedmethanesulfonyl chloride (3.61 mL, 46.99 mmol, 1.2 equiv) slowly. Thereaction mixture was allowed to warm to at room temperature and stirredfor 6 h. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexaneas eluant) to afford 27.2. MS (ES): m/z 181.2 [M+H]⁺.

Synthesis of compound 27.3 and 27.4. Compound 27.3 and 27.4 wereprepared from 27.2 and 19.1 following the procedure described in thesynthesis of compound 19.3 and 19.4. The isomers were separated by flashcolumn chromatography on silica gel (CombiFlash®, 8-12% ethyl acetate inhexane as eluant) to afford 27.3. MS (ES): m/z 302.4 [M+H]⁺ and 27.4. MS(ES): m/z 302.3 [M+H]⁺.

Synthesis of compound I-27. Compound I-27 was prepared from compound27.4 following the procedures described in each step in the synthesis ofI-20. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES):m/z: 503.85 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.48 (s,1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.37-7.35 (d, J=8.4 Hz,1H), 7.17 (s, 1H), 6.82-6.80 (d, J=8.4 Hz, 1H), 6.62-6.61 (d, J=3.6 Hz,1H), 6.51 (s, 1H), 4.50 (bs, 1H), 3.98-3.96 (m, 2H), 3.64 (s, 3H),3.59-3.53 (m, 2H), 2.21-2.16 (m, 2H), 2.04 (s, 3H), 1.79-1.76 (m, 2H),1.40 (s, 9H).

Example 28:N-(4-((2-((5-(tert-butyl)-1-(((1s,3s)-3-hydroxycyclobutyl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 28.2. To a solution of 28.4 (5 g, 39.02 mmol, 1.0equiv) in methanol (25 mL) was added sodium borohydride (2.21 g, 58.53mmol, 1.5 equiv) in small portions at 0° C. The reaction mixture wasallowed to warm to room temperature and stirred for 2 h. It was pouredover ice-water, stirred and pH was adjusted 4-5 by adding 1 Nhydrochloric acid. The mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain 28.2. The crude product was used in the next step without furtherpurification. MS (ES): m/z 131.2 [M+H]⁺.

Synthesis of compound 28.3. To a solution of 28.2 (3.6 g, 27.66 mmol,1.0 equiv) in dichloromethane (36 mL) was added imidazole (2.82 g, 41.49mmol, 1.5 equiv) followed by tert-butyldimethylsilyl chloride (6.22 g,41.49 mmol, 1.5 equiv) and stirred at room temperature for 12 h. It waspoured over saturated sodium bicarbonate solution, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexaneas eluant) to afford 28.3. ¹H NMR (CDCl₃, 400 MHz): δ 4.19-4.14 (m, 1H),3.69 (s, 3H), 2.57-2.46 (m, 3H), 2.25-2.17 (m, 2H), 0.89 (s, 9H), 0.05(s, 6H).

Synthesis of compound 28.4. To a solution of 28.3 (4.1 g, 16.78 mmol,1.0 equiv) in diethyl ether (40 mL) was added lithium aluminum hydridesolution (1 M in THF, 20.1 mL, 20.13 mmol, 1.2 equiv) at 0° C. Thereaction mixture was stirred at room temperature for 2 h. Aftercompletion of reaction, water (4 mL) and 15% sodium hydroxide (12 mL)was added and stirred for 30 min. The reaction mixture was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexaneas eluant) to afford 28.4. ¹H NMR (CDCl₃, 400 MHz): δ 4.22-4.15 (m, 1H),3.66-3.62 (m, 2H), 2.41-2.35 (m, 2H), 2.15-2.11 (m, 1H), 2.02-1.94 (m,1H), 1.73-1.66 (m, 2H), 0.91 (s, 9H), 0.06 (s, 6H).

Synthesis of compound 28.5. To a solution of 28.4 (2.3 g, 10.63 mmol,1.0 equiv) in dichloromethane (25 mL) was added triethylamine (4.44 mL,31.89 mmol, 3.0 equiv) followed by addition of methanesulfonyl chloride(2.45 mL, 31.89 mmol, 3.0 equiv) at 0° C. and stirred at roomtemperature for 3 h. It was poured over ice, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate solution followed brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,12% ethyl acetate in hexane as eluant) to afford 28.5. ¹H NMR (CDCl₃,400 MHz): δ 4.24-4.16 (m, 3H), 3.03 (s, 3H), 2.45-2.39 (m, 1H),2.20-2.14 (m, 1H), 1.78-1.69 (m, 3H), 0.89 (s, 9H), 0.05 (s, 6H).

Synthesis of compound 28.6 and 28.7. To a solution of 19.1 (2.0 g, 9.20mmol, 1.0 equiv) and 28.5 (3.25 g, 11.04 mmol, 1.2 equiv) in DMF (7 mL)was added cesium carbonate (5.98 g, 18.40 mmol, 2.0 equiv) reactionmixture was stirred at 80° C. for 16 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 6-8% ethylacetate in hexane as eluant) to afford 28.6. MS (ES): m/z 416.7 [M+H]⁺and 28.7 (0.500 g, Yield: 13.07%). MS (ES): m/z 416.6 [M+H]⁺.

Synthesis of compound 28.8. A solution of 28.7 (0.500 g, 1.2 mmol, 1.0equiv) and hydroxylamine hydrochloride (0.828 g, 12 mmol, 10 equiv) inethanol:water (2:1, 10 mL) was stirred at 120° C. in a microwave reactorfor 1 h. It was poured over ice-water, neutralized by 2 N sodiumhydroxide and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain chiral mixture whichwas separated by preparative HPLC to obtain 28.8. MS (ES): m/z 224.3[M+H]⁺ and 28.9. MS (ES): m/z 224.2 [M+H]⁺.

Synthesis of compound 28.9. Compound 28.9 was prepared from 28.8following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without purification. MS (ES): m/z266.4 [M+H]⁺.

Synthesis of I-28. Compound I-28 was prepared from compound 28.9following the procedures described in each step in the synthesis of I-1.The product was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES): m/z:504.9 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.39 (s, 1H),8.14-8.13 (d, J=5.2 Hz, 1H), 7.64 (s, 1H), 7.35-7.33 (d, J=8.4 Hz, 1H),7.16 (s, 1H), 6.81-6.78 (d, J=8.4 Hz, 1H), 6.61-6.60 (d, J=4 Hz, 1H),6.50 (s, 1H), 5.02-5.01 (d, J=6.4 Hz, 1H), 4.08-4.07 (d, J=5.2 Hz, 2H),3.93-3.91 (m, 1H), 3.62 (s, 3H), 2.32-2.29 (m, 3H), 2.02 (s, 3H),1.70-1.68 (m, 2H), 1.37 (s, 9H).

Example 29:N-(4-((2-((5-(tert-butyl)-1-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 29.2 To a solution of 29.1 (3.0 g, 16.83 mmol, 1.0equiv) in dichloromethane (30 mL) and triethylamine (3.0 mL, 21.87 mmol,1.3 equiv) at 0° C. was added methanesulfonyl chloride (1.7 mL, 21.87mmol, 1.3 equiv). The reaction mixture was allowed to warm to roomtemperature and stirred for 12 h. It was poured over ice-water, stirredand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 20% ethyl acetate inhexane as eluant) to afford 29.2. MS (ES): m/z 257.3 [M+H]⁺.

Synthesis of compound 29.3, 29.4, 29.5 and 29.6. Compound 29.3, 29.4,29.5 and 29.6 were prepared from compound 19.1 and 29.2 following theprocedure described in the synthesis of compound 19.3 and 19.4. Theisomers were separated by flash column chromatography on silica gel(CombiFlash®, 8-12% ethyl acetate in hexane as eluant). MS (ES): m/z378.5 [M+H]⁺.

Synthesis of compound 29.9. Compound 29.9 was prepared from 29.5following the procedures described in each step in the synthesis ofcompound I-20. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.2% methanol in dichloromethane as eluant).MS (ES): m/z 580.7 [M+H]⁺.

Synthesis of I-29. A mixture of compound 29.9 (0.070 g, 0.120 mmol, 1.0equiv) and 20% palladium hydroxide on carbon (0.150 g) in methanol (5mL) was stirred at rt under 1 atm hydrogen for 12 h. The reactionmixture was filtered through a pad of Celite® and rinsed with methanol.The filtrate was concentrated under reduced pressure and the residue waspurified by flash column chromatography on silica gel (CombiFlash®, 5%methanol in dichloromethane as eluant) to afford I-29. MS (ES): m/z:490.51 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.53 (s, 1H),8.16-8.14 (d, J=5.2 Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d, J=8.0 Hz, 1H),7.19 (s, 1H), 6.83-6.81 (d, J=7.6 Hz, 1H), 6.62-6.61 (d, J=3.6 Hz, 1H),6.50 (s, 1H), 5.19-5.18 (m, 2H), 4.46 (bs, 1H), 3.64 (s, 3H), 2.74 (bs,2H), 2.33 (bs, 2H), 2.03 (s, 3H), 1.36 (s, 9H).

Example 30:N-(4-((2-((5-(tert-butyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-30. Compound I-30 was prepared from 29.6 in thesame manner as that in the synthesis of I-29. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 5% methanolin dichloromethane as eluant). MS (ES): m/z: 490.46 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.53 (s, 1H), 8.15-8.13 (d, J=5.6Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d, J=8.4 Hz, 1H), 7.17 (s, 1H),6.82-6.80 (d, J=7.6 Hz, 1H), 6.61-6.60 (d, J=3.6 Hz, 1H), 6.48 (s, 1H),5.20-5.19 (m, 2H), 4.03-4.01 (m, 1H), 3.63 (s, 3H), 3.50-3.48 (m, 2H),2.62 (bs, 2H), 2.02 (s, 3H), 1.35 (s, 9H).

Example 31:N-(4-((2-((5-(tert-butyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 31.2 and 31.3. To a solution of 31.1 (0.4 g, 2.65mmol, 1.0 equiv) in DMF (5 mL) was added sodium hydride (0.165 g, 3.45mmol, 1.3 equiv) at 0° C. and stirred for 30 min. To the solution wasadded 17.1 (0.0.368 g, 2.65 mmol, 1.0 equiv). The reaction mixture wasstirred at room temperature for 16 h. It was poured over ice, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to obtain 31.2. MS (ES): m/z 210.3 [M+H]⁺ and 31.3. MS(ES): m/z 210.3 [M+H]⁺.

Synthesis of compound 31.4. Compound 31.4 was prepared from 31.2following the procedure described in the synthesis of 11.8. MS (ES): m/z252.3 [M+H]⁺.

Synthesis of I-31. Compound 31.4 was prepared from 31.4 and Int-2following the procedure described in the synthesis of compound I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3-4% methanol in dichloromethane as eluant). MS (ES): m/z489.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.41 (s, 1H),8.15-8.13 (d, J=5.6 Hz, 1H), 7.64 (s, 1H), 7.36-7.34 (d, J=8.4 Hz, 1H),7.17 (s, 1H), 6.82-6.80 (d, J=7.6 Hz, 1H), 6.60 (s, 1H), 6.48 (s, 1H),4.71-4.67 (m, 2H), 4.56-4.54 (m, 2H), 4.42-4.40 (m, 2H), 3.60 (bs, 3H),3.50-3.47 (m, 1H), 2.02 (s, 3H), 1.37 (s, 9H).

Example 32:N-(4-((2-((5-(tert-butyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)amino)-7-cyano-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-32. Compound I-32 was prepared from 31.4 and Int-4following the procedure described in the synthesis of compound I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.0% methanol in dichloromethane as eluant). MS (ES): m/z:515.15 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 9.79 (s, 1H),8.22 (bs, 1H), 7.68-7.58 (m, 2H), 7.04 (bs, 1H), 6.70 (bs, 1H),6.51-6.48 (m, 1H), 4.69 (bs, 2H), 4.54 (bs, 2H), 4.29 (bs, 2H), 3.90 (s,3H), 3.77 (s, 1H), 2.04 (s, 3H), 1.38 (s, 9H).

Example 33:N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 33.1. To a solution of 1,1,1-triethoxyethane (20g, 123.28 mmol, 1.0 equiv) and pyridine (21 mL, 258.8 mmol, 2.1 equiv)in dichloromethane (200 mL) at 0° C. was added trifluoroacetic anhydride(52 g, 246.57 mmol, 2.0 equiv). The reaction solution was allowed towarm to rt and stirred for 16 h. It was poured over saturated sodiumbicarbonate solution, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain 33.1. MS (ES): m/z 213.2 [M+H]⁺.

Synthesis of compound 33.2. To a solution of 33.1 (14.2 g, 66.93 mmol,1.0 equiv) in acetonitrile (150 mL) was added aqueous ammonia solution(28 mL) at 0° C. The reaction mixture was allowed to warm to rt andstirred for 24 h. It was poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain crude which was triturated with n-pentane toobtain 33.2. MS (ES): m/z 184.2 [M+H]⁺.

Synthesis of compound 33.3. To a solution of 33.2 (7.0 g, 38.22 mmol,1.0 equiv) in ethanol (70 mL) was added triethylamine (5.3 mL, 38.22mmol, 1.0 equiv) followed by addition of hydrazine hydrochloride (2.61g, 38.22 mmol, 1.0 equiv). The reaction mixture was heated to reflux for12 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 30% ethyl acetate in hexane as eluant) toafford 33.3. MS (ES): m/z 152.1 [M+H]⁺.

Synthesis of compound 33.4 and 33.5. To a solution of4-(bromomethyl)tetrahydro-2H-pyran (0.7 g, 4.63 mmol, 1.0 equiv) in DMF(8 mL) was added sodium hydride (0.288 g, 6.019 mmol, 1.3 equiv) at 0°C. and stirred for 30 min. To the solution was added 33.3 (0.829 g, 4.63mmol, 1.0 equiv). The reaction mixture was allowed to warm to rt andstirred for 16 h. It was poured over ice, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to obtain 33.4.MS (ES): m/z 250.4 [M+H]⁺ and 33.5. MS (ES): m/z 250.4 [M+H]⁺.

Synthesis of compound 33.6. Compound 33.6 was prepared from 33.4following the procedure described in the synthesis of 11.8. The crudeproduct was used without further purification. MS (ES): m/z 292.3[M+H]⁺.

Synthesis of I-33. Compound I-33 was prepared from 33.6 and Int-2,following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,10% methanol in dichloromethane as eluant). MS (ES): m/z: 530.49 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 10.07 (s, 1H), 8.15-8.13 (d,J=6.0 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J=8.4 Hz, 1H), 7.32 (s, 1H),7.23 (s, 1H), 6.85-6.83 (d, J=6.8 Hz, 1H), 6.61-6.60 (d, J=3.2 Hz, 1H),4.04-4.02 (m, 2H), 3.87-3.84 (m, 2H), 3.67 (s, 3H), 2.20 (bs, 1H), 2.02(s, 3H), 1.56 (bs, 1H), 1.48-1.45 (m, 2H), 1.35-1.23 (m, 3H).

Example 34:N-(4-((7-cyano-1-methyl-2-((1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-34. Compound I-34 was prepared from 33.6 and Int-4,following the procedure described in the synthesis of I-1. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.8% methanol in dichloromethane as eluant). MS (ES): m/z: 555.42[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 10.41 (s, 1H),8.22-8.21 (d, J=5.6 Hz, 1H), 7.75-7.73 (d, J=8.4 Hz, 1H), 7.68 (s, 1H),7.30 (s, 1H), 7.07-7.05 (d, J=8.4 Hz, 1H), 6.71-6.70 (d, J=4 Hz, 1H),4.06-4.04 (m, 2H), 3.94 (s, 3H), 3.87-3.85 (m, 2H), 3.27-3.24 (m, 2H),2.20 (bs, 1H), 2.04 (s, 3H), 1.48-1.45 (m, 2H), 1.35-1.27 (m, 2H).

Example 35:N-(4-((2-((1-(((1s,4s)-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 35.2. To a solution of 35.1 (5.0 g, 34.68 mmol,1.0 equiv) and triethylamine (10.6 mL, 76.29 mmol, 2.2 equiv) in DMF (30mL) was added tert-butyldimethylsilyl chloride (11.5 g, 76.29 mmol, 2.2equiv) and stirred at room temperature for 2 h. It was poured overice-water, acidified with 1 M hydrochloric acid to pH=4, and extractedwith diethyl ether. The organic layer was separated washed with brineand concentrated under reduced pressure to obtain a crude product. Itwas dissolved in a mixture of methanol and THF (1:1, 20 mL) and wasadded a 5 M aqueous solution of sodium hydroxide (10 mL) at roomtemperature. The mixture was stirred for 3 h and was concentrated toone-half volume. It was acidified with 2 M hydrochloric acid to pH=4 andextracted with diethyl ether. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 35.2. MS (ES): m/z 259.4[M+H]⁺.

Synthesis of compound 35.3. To a solution of 35.2 (3.0 g, 11.61 mmol,1.0 equiv) in THF (30 mL) was added a solution of lithium aluminumhydride (1 M in THF, 23.2 mL, 23.2 mmol, 2.0 equiv) at 0° C. Thereaction mixture was allowed to warm to rt and stirred or 3 h. It wascarefully poured over ice-water, neutralized with 1 M hydrochloric acidand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 35.3. MS (ES): m/z 245.5[M+H]⁺.

Synthesis of compound 35.4. To a solution of 35.3 (1.7 g, 6.95 mmol, 1.0equiv) and triethylamine (1.25 mL, 9.035 mmol, 1.3 equiv) indichloromethane (25 mL) was added methanesulfonyl chloride (1.6 mL,20.85 mmol, 1.3 equiv) at 0° C. The reaction solution was allowed towarm to rt and stirred for 12 h. It was poured over ice, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 5% ethyl acetate inhexane as eluant) to afford 35.4. MS (ES): m/z 323.5 [M+H]⁺.

Synthesis of compound 35.5 and 35.6. To a solution of 33.3 (0.6 g, 3.97mmol, 1.0 equiv) in DMF (8 mL) was added sodium hydride (0.247 g, 5.161mmol, 1.3 equiv) at 0° C. and stirred for 30 min. To the mixture wasadded 35.4 (1.28 g, 3.97 mmol, 1.0 equiv). The reaction mixture wasstirred at room temperature for 16 h. It was poured over ice, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to obtain 35.5. MS (ES): m/z 378.5 [M+H]⁺ and 35.6. MS(ES): m/z 378.5 [M+H]⁺.

Synthesis of compound 35.7. Compound 35.7 was prepared from 35.5following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 420.5 [M+H]⁺.

Synthesis of compound 35.8. Compound 35.8 was prepared from 35.5 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2% methanol in dichloromethane as eluant). MS (ES): m/z658.8 [M+H]⁺.

Synthesis of I-35. To a solution of 35.8 (0.062 g, 0.094 mmol, 1.0equiv) in THF (2 mL) was added a solution of tetrabutylammonium fluoride(1 M in THF, 5 mL). The reaction mixture was stirred at 50° C. for 3 h.It was cooled to room temperature, poured over ice-water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 5% methanol indichloromethane as eluant) to afford I-35. MS (ES): m/z: 544.57 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 10.06 (s, 1H), 8.15-8.13 (d,J=5.6 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J=8.4 Hz, 1H), 7.30 (s, 1H),7.23 (s, 1H), 6.85-6.83 (d, J=7.2 Hz, 1H), 6.62-6.60 (d, J=5.2 Hz, 1H),4.57-4.56 (d, 1H), 4.02-3.95 (m, 2H), 3.67 (s, 3H), 3.03 (bs, 1H), 2.02(s, 3H), 1.85-1.82 (m, 2H), 1.55 (bs, 2H), 1.34-1.30 (m, 1H), 1.30 (bs,2H), 1.11-1.03 (m, 2H).

Example 36:(S)—N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(R)—N-(4-((1-methyl-2-((1-((tetrahydro-2H-pyran-3-yl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-36.2 and (±)-36.3. To a solution of 33.3 (0.5g, 3.31 mmol, 1.0 equiv) in DMF (8 mL) was added sodium hydride (0.206g, 4.303 mmol, 1.3 equiv) at 0° C. and stirred for 30 min. To themixture was added 3-(bromomethyl)tetrahydro-2H-pyran ((±)-36.1, 0.592 g,3.31 mmol, 1.0 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was poured over ice, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to obtain(±)-36.2. MS (ES): m/z 250.3 [M+H]⁺ and (±)-36.3. MS (ES): m/z 250.3[M+H]⁺.

Synthesis of compound (±)-36.4. Compound (±)-36.4 was prepared from(±)-36.2 following the procedure as described in the synthesis of 11.8.The crude product was used in the next step without furtherpurification. MS (ES): m/z 292.3 [M+H]⁺.

Synthesis of compound (±)-I-36. Compound (±)-I-36 was prepared from(±)-36.4 and Int-2 following the procedure described in the synthesis ofI-1. MS (ES): m/z 530.5 [M+H]⁺.

I-36-a and I-36-b. Enantiomers of (±)-I-36 were separated on SFC(column: CHIRALCEL OJ-H (250 mm×4.6 mm, 5 μm); eluant: 0.1% DEA inmethanol; flow rate: 4 mL/min) to afford first eluting fraction (I-36-a)and second eluting fraction (I-36-b). (*Absolute stereochemistry notdetermined.)

I-36-a. MS (ES): m/z: 530.44 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.48(s, 1H), 10.06 (s, 1H), 8.15-8.13 (d, J=6 Hz, 1H), 7.64 (s, 1H),7.43-7.41 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.86-6.83 (d, J=10.4 Hz,1H), 6.62-6.60 (d, J=6.4 Hz, 1H), 4.07-4.01 (m, 2H), 3.71 (bs, 1H), 3.67(s, 3H), 3.27-3.23 (m, 2H), 2.19 (bs, 1H), 2.02 (s, 3H), 1.69-1.60 (m,3H), 1.49 (bs, 1H), 1.34-1.23 (m, 1H).

I-36-b. MS (ES): m/z: 530.49 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49(s, 1H), 10.08 (s, 1H), 8.16-8.14 (d, J=6 Hz, 1H), 7.65 (s, 1H),7.44-7.42 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 6.86-6.84 (d,J=8.4 Hz, 1H), 6.62-6.61 (d, J=5.6 Hz, 1H), 4.11-4.00 (m, 2H), 3.71 (bs,1H), 3.68 (s, 3H), 3.28-3.23 (m, 2H), 2.20 (bs, 1H), 2.03 (s, 3H),1.70-1.61 (m, 3H), 1.50 (bs, 1H), 1.34-1.24 (m, 1H).

Example 37:N-(4-((2-((1-(2-oxaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 37.2. To a solution of 37.1 (0.600 g, 5.35 mmol,1.0 equiv) in methanol (10 mL) was added sodium borohydride (0.203 g,5.35 mmol, 1.0 equiv) in small portions at 0° C. The reaction mixturewas stirred at 0° C. for 2 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 37.2. MS (ES): m/z 115.2[M+H]⁺.

Synthesis of compound 37.3. To a solution of 37.2 (0.540 g, 4.73 mmol,1.0 equiv) and triethylamine (1.64 mL, 11.82 mmol, 2.5 equiv) indichloromethane (10 mL) was added methanesulfonyl chloride (0.71 mL,9.46 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 12 h. It was poured over ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 40% ethyl acetate inhexane as eluant) to afford 37.3. MS (ES): m/z 193.2 [M+H]⁺.

Synthesis of compound 37.4 and 37.5. To a solution of 37.3 (0.4 g, 2.08mmol, 1.0 equiv) and 33.3 (0.314 g, 2.08 mmol, 1.0 equiv) in DMF (7 mL)was added cesium carbonate (1.352 g, 4.16 mmol, 2.0 equiv) reactionmixture was stirred at 80° C. for 5 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC to obtain 37.4. MS (ES): m/z 248.2 [M+H]⁺ and 37.5. MS(ES): m/z 248.3 [M+H]⁺.

Synthesis of compound 37.6. Compound 37.6 was prepared from 37.4following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 290.2 [M+H]⁺.

Synthesis of I-37. Compound I-37 was prepared from 37.6 following theprocedure described in the synthesis of I-1. The product was purified byflash column chromatography on silica gel (CombiFlash®, 1.5% methanol indichloromethane as eluant). MS (ES): m/z: 527.8 [M+H]⁺, ¹H NMR (DMSO-d6,400 MHz): δ 10.49 (s, 1H), 10.10 (s, 1H), 8.15-8.13 (d, J=6.0 Hz, 1H),7.64 (s, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.32 (s, 1H), 7.23-7.22 (d,J=1.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.62-6.60 (m, 1H), 4.70 (s, 2H), 4.58(s, 2H), 3.67 (s, 3H), 3.41-3.39 (m, 1H), 2.80-2.78 (m, 4H), 2.02 (s,3H).

Example 38:N-(4-((2-((1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 38.2. To a solution of 38.1 (5.0 g, 29.03 mmol,1.0 equiv) and imidazole (5.0 g, 72.57 mmol, 1.2 equiv) in DMF (25 mL)was added tert-butyldimethylsilyl chloride (5.2 g, 34.83 mmol, 1.2equiv) and stirred at room temperature for 16 h. It was poured oversaturated sodium bicarbonate solution, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 10% ethyl acetate in hexane as eluant) toafford 38.2. MS (ES): m/z 287.5 [M+H]⁺.

Synthesis of compound 38.3. To a solution of 38.2 (4.2 g, 14.66 mmol,1.0 equiv) in diethyl ether (42 mL) was added a solution of lithiumaluminum hydride (1 M in THF, 16.1 mL, 16.12 mmol, 1.1 equiv) at 0° C.The reaction mixture was allowed to warm to rt and stirred for 4 h. Itwas carefully poured over ice, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain 38.3. MS (ES): m/z 245.5 [M+H]⁺.

Synthesis of compound 38.4. Compound 38.4 was prepared from 38.3following the procedure described in the synthesis of 35.4. The productwas purified by flash column chromatography on silica gel (CombiFlash®,12% ethyl acetate in hexane as eluant). MS (ES): m/z 323.5 [M+H]⁺.

Synthesis of compound 38.5 and 38.6. Compounds 38.5 and 38.6 wereprepared from 38.4 and 33.3 following the procedure described in thesynthesis of 35.5 and 35.6. The isomers were isolated by preparativeHPLC to obtain 38.5. MS (ES): m/z 378.5 [M+H]⁺ and 38.6. MS (ES): m/z378.5 [M+H]⁺.

Synthesis of compound 38.7. Compound 38.7 was prepared from 38.5following the procedures described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 420.5 [M+H]⁺.

Synthesis of compound 38.8. Compound 38.8 was prepared from 38.7 andInt-2 following the procedure described in the synthesis of 1-2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2% methanol in dichloromethane as eluant). MS (ES): m/z658.8 [M+H]⁺.

Synthesis of compound I-38. Compound I-38 was prepared from 38.8following the procedure described in the synthesis of I-35. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5% methanol in dichloromethane as eluant). MS (ES): m/z: 544.49 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 10.05 (s, 1H), 8.15-8.13 (d,J=5.6 Hz, 1H), 7.64 (s, 1H), 7.43-7.41 (d, J=8.4 Hz, 1H), 7.30 (s, 1H),7.22 (s, 1H), 6.85-6.83 (d, J=7.2 Hz, 1H), 6.62-6.60 (d, J=5.2 Hz, 1H),4.56-4.55 (d, 1H), 4.04-4.02 (m, 2H), 3.67 (s, 3H), 2.02 (s, 3H),1.85-1.82 (m, 2H), 1.55 (bs, 2H), 1.34-1.30 (m, 1H), 1.30 (bs, 2H),1.11-1.03 (m, 2H).

Example 39:N-(4-((2-((1-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 39.2. To a solution of 39.1 (2.0 g, 9.47 mmol, 1.0equiv) in methanol (20 mL) was added sodium borohydride (1.439 g, 37.88mmol, 4.0 equiv) in small portions at 0° C. The reaction mixture wasstirred at 0° C. for 2 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 39.2. MS (ES): m/z 214.3[M+H]⁺.

Synthesis of compound 39.3. To a solution of 39.2 (1.6 g, 7.5 mmol, 1.0equiv) and triethylamine (1.35 mL, 9.75 mmol, 1.3 equiv) indichloromethane (20 mL) was added methanesulfonyl chloride (0.75 mL,9.75 mmol, 1.3 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 12 h. It was poured over ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to 39.3. MS (ES): m/z 292.3 [M+H]⁺.

Synthesis of compound 39.4 and 39.5. Compound 39.4 and 39.5 wereprepared from 39.3 and 17.1 following the procedure described in thesynthesis of 37.4 and 37.5. The isomers were isolated by preparativeHPLC to obtain 39.4, MS (ES): m/z 347.3 [M+H]⁺ and 39.5, MS (ES): m/z347.3 [M+H]⁺.

Synthesis of compound 39.6. Compound 39.6 was prepared from 39.4following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 389.4 [M+H]⁺.

Synthesis of compound 39.7. Compound 39.7 was prepared from 39.6following the procedure described in the synthesis of 1-2. The productwas purified by flash column chromatography on silica gel (CombiFlash®,1.5% methanol in dichloromethane as eluant). MS (ES): m/z: 627.6 [M+H]⁺.

Synthesis of compound 39.8. To a solution of 39.7 (0.110 g, 0.175 mmol,1.0 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid(0.199 g, 1.75 mmol, 10.0 equiv) at 0° C. The reaction mixture wasstirred at room temperature for 2 h. It was poured over ice-coldsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 39.8. MS (ES): m/z 526.5 [M+H]⁺.

Synthesis of I-39. To a solution of 39.8 (0.074 g, 0.140 mmol, 1.0equiv) and triethylamine (0.058 mL, 0.42 mmol, 1.5 equiv) indichloromethane (3 mL) was added acetic anhydride (0.014 g, 0.140 mmol,1.0 equiv) dropwise at 0° C. The reaction mixture was stirred for 15min. It was poured over ice-water, stirred and extracted withdichloromethane. This was further purified by flash columnchromatography on silica gel (CombiFlash®, 0.5% methanol indichloromethane as eluant) to afford I-39. MS (ES): m/z: 569.5 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 10.14 (s, 1H), 8.15-8.14 (d,J=5.6 Hz, 1H), 7.64-7.40 (m, 2H), 7.32 (s, 1H), 7.23 (s, 1H), 6.86-6.83(d, J=8.8 Hz, 1H), 6.62-6.61 (d, J=4.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.25(s, 1H), 4.14 (s, 1H), 4.05-3.97 (m, 1H), 3.87 (s, 1H), 3.67 (s, 3H),2.82 (s, 3H), 2.74 (bs, 1H), 2.02 (s, 3H), 1.75-1.74 (m, 3H).

Example 40:N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-c]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 40.2. To a solution of 40.1 (10 g, 99.88 mmol, 1.0equiv) and methyl iodide (24.8 mL, 399.52 mmol, 4.0 equiv) in THF (200mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 219 mL,219.7 mmol, 2.2 equiv) at −78° C. The reaction mixture was stirred atroom temperature for 16 h. It was poured over ice-water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexaneas eluant) to afford 40.2. MS (ES): m/z 129.2 [M+H]⁺.

Synthesis of compound 40.3. To a solution of diisopropylamine (4.88 g,48.37 mmol, 1.0 equiv) in THF (100 mL) at −78° C. was slowly added asolution of n-butyl lithium (2.5M in hexane, 24.2 mL, 60.46 mmol, 1.25equiv). The reaction mixture was stirred for 5 min followed by additionof acetonitrile (2.5 mL, 48.37 mmol, 1.0 equiv). The reaction mixturestirred for 10 min and compound 40.3 (6.20 g, 48.37 mmol, 1.0 equiv) inTHF (30 mL) was added to it. The reaction mixture was stirred at 5° C.for 6 h. It was poured over cold saturated ammonium chloride solutionand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 20% ethyl acetate inhexane as eluant) to afford 40.3. MS (ES): m/z 170.2 [M+H]⁺.

Synthesis of compound 40.4. To a solution of 40.3 (3.9 g, 23.05 mmol,1.0 equiv) in ethanol (40 mL) was added hydrazine hydrochloride (2.35 g,34.57 mmol, 1.5 equiv) followed by addition of potassium carbonate (4.77g, 34.57 mmol, 1.5 equiv). The reaction mixture was heated to reflux for16 h. It was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 3-4%methanol in dichloromethane as eluant) to afford 40.4. MS (ES): m/z184.26 [M+H]⁺.

Synthesis of compound 40.5. To a solution of 40.4 (1.1 g, 6.0 mmol, 1.0equiv) in THF (20 mL) was added thionyl chloride (2.15 mL, 30 mmol, 5.0equiv). The reaction mixture was stirred at room temperature for 2 h. Itwas poured over saturated sodium bicarbonate solution, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2% methanol indichloromethane as eluant) to afford 40.5. MS (ES): m/z 166.24 [M+H]⁺.

Synthesis of compound 40.6. Compound 40.6 was prepared from 40.5following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 208.3 [M+H]⁺.

Synthesis of compound I-40. Compound I-40 was prepared from 40.6following the procedure described in the synthesis of I-1. The productwas purified by preparative HPLC. MS (ES): m/z: 446.41 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.48 (s, 1H), 8.15-8.14 (d, J=5.6Hz, 1H), 7.65 (s, 1H), 7.38-7.36 (d, J=8 Hz, 1H), 7.16 (s, 1H),6.82-6.80 (d, J=7.6 Hz, 1H), 6.61-6.56 (m, 2H), 3.94 (bs, 2H), 3.62 (s,3H), 2.03 (s, 6H), 1.68 (s, 3H), 1.25 (bs, 4H).

Example 41:N-(4-((7-cyano-2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-41. Compound I-41 was prepared from 40.6 and Int-4following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5-7% methanol in dichloromethane as eluant). MS (ES): m/z: 470.83[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 9.85 (s, 1H),8.22-8.20 (d, J=5.6 Hz, 1H), 7.68 (bs, 2H), 7.03-7.01 (d, J=8.4 Hz, 1H),6.69 (bs, 1H), 6.55 (s, 1H), 4.02-3.90 (m, 4H), 2.04 (s, 6H), 1.67 (bs,2H), 1.30 (bs, 6H).

Example 42:N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-c]pyridin-2-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-42. Compound I-42 was prepared from 40.6 and Int-5following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,5-6% methanol in dichloromethane as eluant). MS (ES): m/z: 447.45[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1H), 9.79 (s, 1H),8.19-8.17 (d, J=5.6 Hz, 1H), 7.81-7.75 (m, 2H), 6.84-6.82 (d, J=8 Hz,1H), 6.71-6.70 (t, 1H), 6.58 (s, 1H), 5.76 (s, 1H), 3.95-3.93 (m, 2H),3.58 (s, 3H), 2.04 (bs, 4H), 1.67 (bs, 2H), 1.30 (bs, 6H).

Example 43:N-(4-((2-((5,5-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 43.2. To a solution of3,3-dimethylcyclohexan-1-one (43.1, 6.0 g, 47.54 mmol, 1.0 equiv) inethanol (60 mL) was added thiourea (10.86 g, 142 mmol, 3.0 equiv)followed by iodine (12.02 g, 47.54 mmol, 1.0 equiv). The reactionmixture was heated to reflux for 8 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 25% ethyl acetate inhexane as eluant) to afford 43.2. MS (ES): m/z 183.3 [M+H]⁺.

Synthesis of compound 43.3. To a solution of 43.2 (0.200 g, 1.1 mmol,1.0 equiv) in acetonitrile (4 mL) was added thiocarbonyldiimidazole(0.214, 1.208 mmol, 1.1 equiv). The reaction mixture was stirred at roomtemperature for 2 h. After completion of reaction, precipitated solidwas filtered out, dried well to obtain 43.3. MS (ES): m/z 293.4 [M+H]⁺.

Synthesis of I-43. To a solution of 43.3 (0.100 g, 0.349 mmol, 1.0equiv) and Int-3 (0.122 g, 0.417 mmol, 1.2 equiv) in DMF (2 mL) wasadded N,N-diisopropylethylamine (0.2 mL, 1.047 mmol, 3.0 equiv). Thereaction mixture was stirred at 70° C. for 6 h. It was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5% methanol in dichloromethane as eluant) to afford I-43.MS (ES): m/z: 477.81 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 11.83 (s, 1H),10.47 (s, 1H), 8.13-8.11 (d, J=5.2 Hz, 1H), 7.59 (s, 1H), 7.28 (s, 1H),6.79 (s, 1H), 6.53 (s, 1H), 3.87 (s, 3H), 2.43-2.42 (m, 2H), 2.27 (s,3H), 2.03-2.02 (d, 3H), 1.55 (bs, 2H), 1.00 (s, 6H), 0.99-0.84 (m, 2H).

Example 44:N-(4-((2-((6,6-dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 44.2. Compound 44.2 was prepared from4,4-dimethylcyclohexan-1-one (44.1) following the procedure described inthe synthesis of 43.2. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 30% ethyl acetate in hexaneas eluant). MS (ES): m/z 183.3 [M+H]⁺.

Synthesis of compound 44.3. Compound 44.3 was prepared from 44.2following the procedure described in the synthesis of 43.3. The crudeproduct was used in the next step without further purification. MS (ES):m/z 293.4 [M+H]⁺.

Synthesis of I-44. A solution of 44.3 (0.100 g, 0.349 mmol, 1.0 equiv),Int-3 (0.113 g, 0.384 mmol, 1.1 equiv) and N,N-diisopropylethylamine(0.2 mL, 1.047 mmol, 3.0 equiv) in DMF (2 mL) was stirred at 70° C. for12 h under nitrogen. It was cooled to room temperature, poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC to obtain I-44. MS (ES): m/z: 477.81 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 11.88 (s, 1H), 10.49 (s, 1H), 8.14-8.13 (d, J=5.6Hz, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.81-6.79 (d, J=8.4 Hz, 1H),6.55-6.53 (m, 1H), 3.88 (s, 3H), 2.43 (bs, 4H), 2.34 (s, 3H), 2.03 (s,3H), 1.58-1.55 (m, 2H), 1.01 (s, 6H).

Example 45: (R)—N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-c]pyridin-6-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((1-methyl-2-((2-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 45.2. To a solution of 45.1 (8.0 g, 36.36 mmol,1.0 equiv) in ethanol (50 mL) was added 1-chloropropan-2-one (5.05 g,54.54 mmol, 1.5 equiv). The reaction mixture was heated to reflux for 24h. It was concentrated under reduced pressure. The residue was taken inwater and basified to pH 8 with saturated sodium carbonate solution. Theaqueous solution was extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,50% ethyl acetate in hexane as eluant) to afford 45.2. MS (ES): m/z259.2 [M+H]⁺.

Synthesis of compound 45.3. To a solution of 45.2 (4.8 g, 18.16 mmol,1.0 equiv) in acetonitrile (100 mL) was added (diacetoxyiodo)benzene(11.69 g, 36.32 mmol, 2.0 equiv), cesium fluoride (11.04 g, 72.64 mmol,4.0 equiv) followed by trifluoromethyltrimethylsilane (10.314 g, 72.64mmol, 4.0 equiv) and stirred at room temperature for 4 h. It wasfiltered with Celite® bed and washed with ethyl acetate. The filtratewas concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 12% ethylacetate in hexane as eluant) to afford 45.3. MS (ES): m/z 327.2 [M+H]⁺.

Synthesis of compound 45.4. A mixture of 45.3 (1.7 g, 5.21 mmol, 1.0equiv), diphenylmethanimine (1.037 g, 5.73 mmol, 1.1 equiv) and cesiumcarbonate (3.39 g, 10.42 mmol, 2.0 equiv) in DMF (20 mL) was degassed bybubbling argon through for 10 min. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.090 g, 0.156 mmol, 0.03equiv) and tris (dibenzylideneacetone) dipalladium (0, 0.071 g, 0.078mmol, 0.015 equiv) was added, and degassed for 5 min. The reactionmixture was stirred at 80° C. for 4 h. It was cooled to roomtemperature, filtered through a pad of Celite®. The filtrate was pouredover water, extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 15% ethylacetate in hexane as eluant) to afford 45.4. MS (ES): m/z 380.4 [M+H]⁺.

Synthesis of compound 45.5. To a solution of 45.4 (1.62 g, 4.27 mmol,1.0 equiv) in THF (16 mL) was added 1N hydrochloric acid (16 mL, 10 v)and stirred at room temperature for 30 min. It was poured overice-water, stirred and extracted with ethyl acetate. Aqueous layerseparated, neutralized with saturated sodium bicarbonate solution andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 45.5. MS (ES): m/z 216.2[M+H]⁺.

Synthesis of compound 45.6. A mixture of compound 45.5 (0.500 g, 2.32mmol, 1.0 eq), 10% palladium on carbon (0.500 g) in methanol (10 mL) wasstirred at 90° C. under 280 psi hydrogen for 12 h. After completion ofthe reaction, the reaction mixture was filtered through a pad of Celite®and rinsed with methanol. The filtrate was concentrated under reducedpressure to obtain 45.6. MS (ES): m/z 220.2 [M+H]⁺.

Synthesis of compound (±)-45.7. Compound (±)-45.7 was prepared from 45.6following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 262.3 [M+H]⁺.

Synthesis of compound (±)-I-45. Compound (±)-I-45 was prepared from(±)-45.6 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.0% methanol in dichloromethane as eluant) to afford. MS(ES): m/z: 500.5 [M+H]⁺.

I-45-a and I-45-b. Enantiomers of I-45 were isolated by SFC (CHIRALPAKAD-H (250 mm×4.6 mm, 5 μm), eluent: 0.1% DEA in MEOH; flow rate: 4mL/min) to get first eluting fraction (I-45-a) and second elutingfraction (I-45-b). (*Absolute stereochemistry not determined.)

I-45-a: MS (ES): m/z: 500.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.47(s, 1H), 8.13-8.12 (d, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.29-7.27 (d, J=8.4Hz, 1H), 7.11 (s, 1H), 6.90-6.88 (d, J=6.4 Hz, 1H), 6.78-6.75 (m, 1H),6.59-6.58 (m, 1H), 4.43 (bs, 1H), 4.37-4.33 (m, 1H), 4.06-3.97 (m, 2H),3.51 (s, 3H), 2.99-2.85 (m, 2H), 2.22 (bs, 3H), 2.15-2.10 (m, 1H), 2.02(s, 3H).

I-45-b: MS (ES): m/z: 500.77 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.46(s, 1H), 8.13-8.12 (d, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.29-7.27 (d, J=8.4Hz, 1H), 7.11 (s, 1H), 6.89-6.88 (d, J=6.4 Hz, 1H), 6.78-6.76 (m, 1H),6.59-6.58 (m, 1H), 4.43 (bs, 1H), 4.37-4.33 (m, 1H), 4.04-3.97 (m, 2H),3.51 (s, 3H), 2.99-2.89 (m, 2H), 2.22 (bs, 3H), 2.13-2.12 (m, 1H), 2.02(s, 3H).

Example 46:N-(4-((2-((2-acetyl-5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 46.2 To a solution of 46.1 (5.0 g, 35.94 mmol, 1.0equiv) in concentrated sulfuric acid (20 mL) was added potassium nitrate(4.17 g, 41.35 mmol, 1.1 equiv) at 0° C. The reaction mixture wasstirred at room temperature for 3 h. It was poured over crushed ice,neutralized by aqueous ammonium hydroxide, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 3-4% methanol in dichloromethane as eluant) toafford 46.2. MS (ES): m/z 179.2 [M+H]⁺.

Synthesis of compound 46.3. To a solution of 46.2 (1.3 g, 7.30 mmol, 1.0equiv) in triflic acid (2.5 mL) was added N-iodo-succinimide (1.97 g,8.76 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 3 h. It was poured over cold saturated sodiumbicarbonate solution and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,3% methanol in dichloromethane as eluant) to afford 46.3. MS (ES): m/z305.1 [M+H]⁺.

Synthesis of compound 46.4. To a solution of 46.3 (0.9 g, 2.96 mmol, 1.0equiv) in THF (20 mL) was added triethylamine (1.23 mL, 8.88 mmol, 3.0equiv) followed by addition of acetyl chloride (0.25 mL, 3.55 mmol, 1.2equiv) at 0° C. and stirred at room temperature for 4 h. It was cooledto room temperature poured over water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 60% ethyl acetate in hexane as eluant) toafford 46.4. MS (ES): m/z 347.12 [M+H]⁺.

Synthesis of compound 46.5. To a mixture of 46.4 (0.350 g, 1.01 mmol,1.0 equiv), copper(II) chloride (0.027 g, 0.202 mmol, 0.2 equiv), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (0.582 g, 3.03 mmol, 3.0 equiv)in N,N-dimethylformamide (10 mL) was heated at 120° C. by a microwavereactor for 2 h. The reaction mixture was transferred into saturatedsodium bicarbonate solution, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 30% ethyl acetate in hexane as eluant). MS (ES): m/z289.23 [M+H]⁺.

Synthesis of compound 46.6. A mixture of compound 46.5 (0.155 g, 0.537mmol, 1.0 equiv) and 10% palladium on carbon (0.050 g) in ethanol (10mL) was vacuumed and purged with hydrogen three times. The reactionmixture was stirred at rt under 1 atm hydrogen for 2 h. It was filteredthrough a pad of Celite® and rinsed with methanol. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel (CombiFlash®, 5% methanol indichloromethane as eluant) to afford 46.6. MS (ES): m/z 259.24 [M+H]⁺.

Synthesis of compound 46.7. Compound 46.7 was prepared from 46.6following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 301.3 [M+H]⁺.

Synthesis of I-46. Compound I-46 was prepared from 46.7 following theprocedure described in the synthesis of I-1. The product was purified byflash column chromatography on silica gel (CombiFlash®, 5% methanol indichloromethane as eluant). MS (ES): m/z: 539.57 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 9.29 (s, 1H), 8.16 (bs, 2H), 8.10(s, 1H), 7.66 (s, 1H), 7.50-7.48 (d, J=7.6 Hz, 1H), 7.27 (s, 1H),6.89-6.87 (d, J=8 Hz, 1H), 6.63 (s, 1H), 4.77-4.70 (m, 2H), 3.71 (bs,5H), 2.96 (bs, 1H), 2.83 (bs, 1H), 2.14-2.11 (d, 3H), 2.00 (s, 3H).

Example 47:N-(4-((2-((1-(2-methoxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indolin-6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 47.2. To a solution of 47.1 (10 g, 4.90 mmol, 1.0equiv) in sulfuric acid (10 mL) was added solution of N-iodosuccinimide(1.32 g, 5.88 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirredat room temperature for 12 h. It was carefully poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 47.2. MS (ES): m/z332.2 [M+H]⁺.

Synthesis of compound 47.3. Dimethyl oxalate (4.27 g, 36.25 mmol, 1.0equiv) was added to sodium methoxide solution (21%) in methanol (9.3 mL,36.25 mmol, 1.0 equiv) at room temperature and stirred for 1.5 h. To themixture was added a solution of 47.2 (12 g, 36.25 mmol, 1.0 equiv) inmethanol (10 mL) and stirred at room temperature for 12 h. It was addedto ice-cold 2.5 M hydrochloric acid until pH 4-5, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexaneas eluant) to afford 47.3. MS (ES): m/z 418.2 [M+H]⁺.

Synthesis of compound 47.4. To a solution of 47.3 (10 g, 23.98 mmol, 1.0equiv) in acetic acid (20 mL) was added perchloric acid (10 mL) at rt.The mixture was heated at 80° C. for 1 h. It was cooled to roomtemperature and added 30% hydrogen peroxide solution (59 mL, 527 mmol,22 equiv). The reaction mixture was stirred at 60° C. for 5 h. It waspoured over a saturated aqueous sodium sulphite solution, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine and 2 N sodium hydroxide solution Aqueous layer was acidifiedwith conc. hydrochloric acid to pH 3. The precipitates were collected byfiltration, rinsed with water and dried under vacuum to afford 47.4. MS(ES): m/z 376.1 [M+H]⁺.

Synthesis of compound 47.5. To a solution of 47.4 (2.5 g, 6.67 mmol, 1.0equiv) in methanol (25 mL) was added oxalyl chloride (3.75 mL, 43.7mmol, 6.5 equiv). The reaction mixture was stirred at 70° C. for 4 h. Itwas poured over saturated sodium bicarbonate solution, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 20% ethyl acetate inhexane as eluant) to afford 47.5. MS (ES): m/z 390.1 [M+H]⁺.

Synthesis of compound 47.6. To a solution of 47.5 (2.0 g, 5.14 mmol, 1.0equiv) in methanol (20 mL) was added a commercial 15% titanium (III)chloride solution (9.8 g, 63.73 mmol, 12.4 equiv) at 0° C. The reactionmixture was stirred at room temperature for 12 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,10% ethyl acetate in hexane as eluant) to afford 47.6. MS (ES): m/z328.2 [M+H]⁺.

Synthesis of compound 47.7. To a solution of 47.6 (1.4 g, 4.28 mmol, 1.0equiv) in THF (15 mL) was added potassium tert-butoxide (2.39 g, 21.4mmol, 5.0 equiv) at 0° C. followed by copper (I) bromide dimethylsulfide complex (0.087 g, 0.428 mmol, 0.1 equiv). Methyl iodide (1.27 g,8.98 mmol, 2.1 equiv) was slowly added at 0° C. The reaction mixture wasstirred at room temperature for 3 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 8% ethyl acetatein hexane as eluant) to afford 47.7. MS (ES): m/z 356.1 [M+H]⁺.

Synthesis of compound 47.8. To a solution of 47.7 (0.5 g, 1.41 mmol, 1.0equiv) and 2-methoxyethyl methanesulfonate (0.260 g, 1.69 mmol, 1.2equiv) in DMF (5 mL) was added cesium carbonate (1.14 g, 3.52 mmol, 2.5equiv) reaction mixture was stirred at 80° C. for 16 h. It was pouredover ice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,5-8% ethyl acetate in hexane as eluant) to afford 47.8. MS (ES): m/z414.5 [M+H]⁺.

Synthesis of compound 47.9. To a solution of 47.8 (0.370 g, 0.895 mmol,1.0 equiv) in dimethyl sulfoxide (4 mL) was added L-proline (0.020 g,0.179 mmol, 0.2 equiv), copper iodide (0.068 g, 0.358 mmol, 0.4 equiv)and potassium carbonate (0.432 g, 3.13 mmol, 3.5 equiv) followed byammonium hydroxide solution (0.13 mL). The reaction mixture was stirredat 90° C. for 16 h. It was cooled to room temperature, poured overwater, extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 25% ethyl acetate inhexane as eluant) to afford 47.9. MS (ES): m/z 303.3 [M+H]⁺.

Synthesis of compound 47.10. Compound 47.10 was prepared from 47.9following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 345.4 [M+H]⁺.

Synthesis of I-47. Compound I-47 was prepared from 47.10 and Int-2following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,3-5% methanol in dichloromethane as eluant). MS (ES): m/z: 583.9 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 9.42 (s, 1H), 8.16-8.15 (d,J=6.0 Hz, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.45-7.43 (d,J=8.4 Hz, 1H), 7.28 (s, 1H), 6.89-6.87 (d, J=7.2 Hz, 1H), 6.63-6.62 (d,J=3.6 Hz, 1H), 3.90-3.89 (m, 2H), 3.72 (s, 3H), 3.65-3.62 (m, 2H), 3.24(s, 3H), 2.03 (s, 3H), 1.36 (s, 6H).

Example 48:N-(4-((2-((1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-4-(trifluoromethyl)indolin-6-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 48.2. To a solution of 48.1 (1.0 g, 6.57 mmol, 1.0equiv) and triethylamine (2.74 mL, 19.71 mmol, 3.0 equiv) indichloromethane (10 mL) was added methanesulfonyl chloride (0.76 mL,9.85 mmol, 1.5 equiv) at 0° C. The reaction mixture was stirred at roomtemperature for 3 h. It was poured over ice-water, stirred and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to obtain 48.2. MS (ES): m/z 231.3 [M+H]⁺.

Synthesis of compound 48.3. Compound 48.3 was prepared from 48.1 and47.7 following the procedure described in the synthesis of 47.8. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 10-12% ethyl acetate in hexane as eluant). MS (ES): m/z490.3 [M+H]⁺.

Synthesis of compound 48.4. Compound 48.4 was prepared from 48.3following the procedure described in the synthesis of 47.9. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,20-22% ethyl acetate in hexane as eluant). MS (ES): m/z 379.4 [M+H]⁺.

Synthesis of compound 48.5. Compound 48.5 was prepared from 48.4following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 421.5 [M+H]⁺.

Synthesis of compound 48.6. Compound 48.6 was prepared from 48.5following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,3-4% methanol in dichloromethane as eluant). MS (ES): m/z: 659.6 [M+H]⁺.

Synthesis of compound I-48. To a solution of compound 48.6 (0.100 g,0.151 mmol, 1.0 equiv) in dichloromethane (5 mL) was added triflic acid(0.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min.It was poured over saturated sodium bicarbonate solution and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by trituration withmethanol to obtain I-48. MS (ES): m/z: 569.9 [M+H]⁺, ¹H NMR (DMSO-d6,400 MHz): δ 10.50 (s, 1H), 9.42 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H),8.03 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.47-7.45 (d, J=8.4 Hz, 1H),7.29 (s, 1H), 6.89-6.87 (d, J=8.4 Hz, 1H), 6.64-6.63 (d, J=3.6 Hz, 1H),4.99-4.97 (m, 1H), 3.79-3.78 (m, 2H), 3.72 (s, 3H), 3.70-3.67 (m, 2H),2.02 (s, 3H), 1.37 (s, 6H).

Example 49:N-(4-((1-methyl-2-((1,1,2-trimethyl-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 49.2. To a solution of 49.1 (1.0 g, 4.90 mmol, 1.0equiv) in 0.2 M aqueous acetic acid (20 mL) was added nitric acid (2.08mL, 49 mmol, 10 equiv), bromine (0.86 g, 5.39 mmol, 1.1 equiv) followedby addition of 2.5 M aqueous silver nitrate solution (2.5 mL, 6.37 mmol,1.3 equiv) over a period of 30 min. The reaction mixture was stirred atroom temperature for 48 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 49.2. MS (ES): m/z 284.1[M+H]⁺.

Synthesis of compound 49.3. To a solution of 49.2 (1.6 g, 5.65 mmol, 1.0equiv) in methanol (20 mL) was added thionyl chloride (0.82 mL, 11.3mmol, 2.0 equiv) at 0° C. The reaction mixture was heated to reflux for4-5 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 49.3. MS (ES): m/z 298.1 [M+H]⁺.

Synthesis of compound 49.4. To a solution of 49.3 (0.710 g, 2.39 mmol,1.0 equiv) in carbon tetrachloride (10 mL) was added N-bromosuccinimide(0.425 g, 2.39 mmol, 1.0 equiv) followed by azobisisobutyronitrile(0.078 g, 0.478 mmol, 0.2 equiv). The reaction mixture was heated toreflux for 1 h. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 49.4. MS (ES): m/z 362.9 [M+H]⁺.

Synthesis of compound 49.5. To a solution of 49.4 (0.480 g, 1.33 mmol,1.0 equiv) in methanol (5 mL) and THF (5 mL) was added aqueous ammoniumhydroxide solution (2.5 mL). The reaction mixture was stirred at 50° C.heated to reflux for 4 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.0% methanol indichloromethane as eluant) to afford 49.5. MS (ES): m/z 281.1 [M+H]⁺.

Synthesis of compound 49.6. To a solution of 49.5 (0.205 g, 0.732 mmol,1.0 equiv) in THF (3 mL) was added sodium hydride (0.175 g, 3.66 mmol,5.0 equiv) in small portions at 0° C. and stirred for 20 min. To themixture was added methyl iodide (0.620 g, 4.39 mmol, 6.0 equiv). Thereaction mixture was stirred at room temperature for 24 h. It was pouredover ice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,17% ethyl acetate in hexane as eluant) to afford 49.6. MS (ES): m/z323.2 [M+H]⁺.

Synthesis of compound 49.7. Compound 49.7 was prepared from 49.6following the procedure described in the synthesis of 47.9. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,30% ethyl acetate in hexane as eluant) to afford 49.7. MS (ES): m/z259.3 [M+H]⁺.

Synthesis of compound 49.8. Compound 49.8 was prepared from 49.7following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 301.3 [M+H]⁺.

Synthesis of compound I-49. Compound I-49 was prepared from 49.8following the procedure described in the synthesis of I-1. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,4.2% methanol in dichloromethane as eluant). MS (ES): m/z: 539.5 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1H), 9.60 (s, 1H), 8.71 (s, 1H),8.44 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.66 (s, 1H), 7.55-7.53 (d,J=8.4 Hz, 1H), 7.31 (s, 1H), 6.91-6.89 (d, J=6.4 Hz, 1H), 6.63-6.62 (d,J=3.6 Hz, 1H), 3.74 (s, 3H), 2.99 (s, 3H), 2.02 (s, 3H), 1.52 (s, 6H).

Example 50: (R)—N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamideand (S)—N-(4-((2-((5-(tert-butyl)isoxazol-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)-2,2-difluorocyclopropane-1-carboxamide

Synthesis of compound (±)-50.1. To a solution of Int-1.3 (1.0 g, 4.99mmol, 1.0 equiv) and 2,2-difluorocyclopropane-1-carboxylic acid (0.913g, 7.485 mmol, 1.5 equiv) in THF (10 mL) was addedN,N-diisopropylethylamine (2.17 mL, 12.48 mmol, 2.5 equiv) and stirredat room temperature for 30 min. To the mixture was addedpropylphosphonic anhydride (˜50% in ethyl acetate, 2.38 g, 7.485 mmol,1.5 equiv) at 0° C. The reaction mixture was stirred at room temperaturefor 2 h. It was poured over ice water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20-25% ethyl acetate in hexane as eluant) toafford (±)-50.1. MS (ES): m/z 305.3 [M+H]⁺.

Synthesis of compound (±)-50.2. A mixture of compound (±)-50.1 (0.75 g,2.46 mmol, 1.0 equiv) and 10% palladium on carbon (0.3 g) in methanol(15 mL) was added vacuumed and purged with hydrogen three times. Thereaction mixture was stirred at rt under 1 atm hydrogen for 2 h. It wasfiltered through a pad of Celite® and rinsed with methanol. The filtratewas concentrated under reduced pressure and the residue was purified byflash column chromatography on silica gel (CombiFlash®, 30-35% ethylacetate in hexane as eluant) to afford (±)-50.2. MS (ES): m/z 215.2[M+H]⁺.

Synthesis of compound (±)-50.3. Compound (±)-50.3 was prepared from(±)-50.2 and Int-2.2 following the procedure described in the synthesisof Int-2.3. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 25-30% ethyl acetate in hexane as eluant). MS(ES): m/z 365.3 [M+H]⁺.

Synthesis of compound (±)-50.4. Compound (±)-50.4 was prepared from(±)-50.3 following the procedure described in the synthesis of Int-2.The product was purified by flash column chromatography on silica gel(CombiFlash®, 35-40% ethyl acetate in hexane as eluant). MS (ES): m/z335.3 [M+H]⁺.

Synthesis of compound (±)-I-50. Compound (±)-I-50 was prepared fromcompound (±)-50.4 and compound 1.2 following the procedure described inthe synthesis of I-1. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 1% methanol indichloromethane as eluant). MS (ES): m/z: 483.7 [M+H]⁺.

I-50-a and I-50-b. Enantiomers of 1.7 (0.090 g) were separated using SFC(CHIRALCEL OJ-H (250 mm×4.6 mm, 5 μm); eluent: 0.1% DEA in MEOH:ACN(50:50); flow rate=4 mL/min) to get first eluting fraction (I-50-a) andsecond eluting fraction (I-50-b). (*Absolute stereochemistry notdetermined.)

I-50-a. MS (ES): m/z: 483.76 [M+H]⁺, ¹H NMR (MeOD, 400 MHz): δ 8.17-8.16(d, J=5.6 Hz, 1H), 7.69 (s, 1H), 7.43 (bs, 1H), 7.15 (s, 1H), 6.95-6.93(d, J=7.2 Hz, 1H), 6.73-6.71 (m, 1H), 5.99 (s, 1H), 3.63 (s, 3H),2.84-2.76 (m, 1H), 2.09-2.01 (m, 1H), 1.87-1.78 (m, 1H), 1.39 (s, 9H).

I-50-b. MS (ES): m/z: 483.76 [M+H]⁺, ¹H NMR (MeOD, 400 MHz): δ 8.17-8.16(d, J=5.6 Hz, 1H), 7.68 (s, 1H), 7.43 (bs, 1H), 7.15 (s, 1H), 6.95-6.93(d, J=7.2 Hz, 1H), 6.73-6.71 (m, 1H), 6.00 (s, 1H), 3.63 (s, 3H),2.84-2.76 (m, 1H), 2.09-2.01 (m, 1H), 1.87-1.78 (m, 1H), 1.39 (s, 9H).

Example 51:N-(4-((2-(((1r,4r)-4-(tert-butyl)cyclohexyl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 51.2 and 51.3. A mixture of4-(tert-butyl)cyclohexan-1-one (51.1, 10 g, 64.83 mmol, 1.0 equiv),benzylamine (8.32 g, 77.79 mmol, 1.2 equiv) and molecular sieves (5.0 g)in methanol (100 mL) was stirred at room temperature for 16 h. To thereaction mixture was added sodium borohydride (4.9 g, 129.6 mmol, 2.0equiv) in small portions at 0° C. It was allowed to warm to roomtemperature and stirred for 6 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 20% ethyl acetate inhexane as eluant) to afford 51.2. MS (ES): m/z 246.4 [M+H]⁺ and 51.3. MS(ES): m/z 246.4 [M+H]⁺.

Synthesis of compound 51.4. A mixture of compound 51.3 (3.9 g, 15.89mmol, 1.0 equiv) and 10% palladium on carbon (2.0 g) in methanol (40 mL)was vacuumed and purged with 1 atm hydrogen and stirred at rt for 16 h.It was vacuumed and purged with nitrogen before opened to air. Themixture was filtered through a pad of Celite® and rinsed with methanol.The filtrate was concentrated under reduced pressure to obtain 51.4. MS(ES): m/z 156.2 [M+H]⁺.

Synthesis of compound 51.5. Compound 51.5 was prepared from 51.4following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 198.3 [M+H]⁺.

Synthesis of I-51. Compound I-51 was prepared from 51.5 and Int-2following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,3.5% methanol in dichloromethane as eluant). MS (ES): m/z: 436.5 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.47 (s, 1H), 8.13-8.12 (d, J=6.0 Hz, 1H),7.62 (s, 1H), 7.22-7.20 (d, J=8.4 Hz, 1H), 7.04 (bs, 1H), 6.84-6.82 (d,J=8.0 Hz, 1H), 6.74-6.72 (d, J=6.8 Hz, 1H), 6.59-6.57 (m, 1H), 3.65-3.63(m, 1H), 3.47 (s, 3H), 2.13-2.10 (m, 2H), 2.03 (s, 3H), 1.82-1.79 (m,2H), 1.56 (bs, 1H), 1.35-1.26 (m, 2H), 1.17-1.02 (m, 2H), 0.88 (s, 9H).

Example 52:N-(4-((2-((1-(2-methoxyethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)methyl)pyridin-2-yl)acetamide

Synthesis of compound 52.2. To a solution of 52.1 (5.0 g, 30.66 mmol,1.0 equiv) in conc. sulfuric acid (25 mL) was added fuming nitric acid(8 mL) at 0° C. The reaction mixture was stirred at 65° C. for 6 h. Itwas poured over crushed ice, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant) to afford52.2. MS (ES): m/z 209.10 [M+H]⁺.

Synthesis of compound 52.3. A mixture of 52.2 (1.0 g, 4.81 mmol, 1.0equiv) and potassium carbonate (1.3 g, 9.62 mmol, 2.0 equiv) in DMF (15mL) was stirred at rt for 15 min. 1-Bromo-2-methoxyethane (1.0 g, 7.21mmol, 1.5 equiv) was added and the reaction mixture was stirred at 70°C. for 2 h. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane as eluant) toafford 52.3. MS (ES): m/z 267.2 [M+H]⁺.

Synthesis of compound 52.4. A flask charged with compound 52.3 (0.6 g,2.25 mmol, 1.0 equiv), 10% palladium on carbon (0.3 g) and methanol (18mL) was vacuumed and purged with hydrogen three times. The mixture wasstirred at rt under 1 atm hydrogen atmosphere for 1 h. The flask wasvacuumed and purged with nitrogen three times before it was opened toair. The reaction mixture was filtered through a pad of Celite® andrinsed with methanol. The filtrate was concentrated under reducedpressure to obtain 52.4. MS (ES): m/z 237.2 [M+H]⁺.

Synthesis of compound 52.5. Compound 52.5 was prepared from 52.4following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 279.3 [M+H]⁺.

Synthesis of I-52. Compound I-52 was synthesized from compound 52.5 andInt-2 following the synthetic protocol described in the synthesis ofI-12. The product was purified by preparative HPLC. MS (ES): m/z: 517.92[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 8.65 (s, 1H), 8.53(s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.65 (s, 1H),7.58-7.56 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 6.92-6.90 (d, J=7.6 Hz, 1H),6.62-6.61 (d, J=3.6 Hz, 1H), 4.29-4.28 (m, 2H), 3.73 (s, 3H), 3.70-3.67(t, 2H), 3.28 (s, 3H), 2.02 (s, 3H).

Example 53:N-(4-((7-cyano-2-((1-(2-methoxyethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-53. Compound I-53 was prepared from 52.5 andInt-4 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 1.8% methanol in dichloromethane as eluant). MS (ES): m/z:542.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.64 (s, 1H), 8.82 (s, 1H),8.59 (s, 1H), 8.24-8.23 (d, J=5.6 Hz, 1H), 8.00 (s, 1H), 7.92-7.90 (d,J=8.4 Hz, 1H), 7.71 (s, 1H), 7.14-7.12 (d, J=8.8 Hz, 1H), 6.74-6.72 (m,1H), 4.32-4.30 (t, 2H), 3.97 (s, 3H), 3.71-3.68 (t, 2H), 3.28 (s, 3H),2.05 (s, 3H).

Example 54:N-(4-((1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 54.2. A mixture of 54.1 (1.0 g, 4.81 mmol, 1.0equiv), potassium carbonate (1.3 g, 9.62 mmol, 2.0 equiv) and methyliodide (1.0 g, 7.21 mmol, 1.5 equiv) in DMF (15 mL) was stirred at 70°C. for 2 h. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane as eluant) toafford 54.2. MS (ES): m/z 223.12 [M+H]⁺.

Synthesis of compound 54.3. Compound 54.3 was prepared from 54.2following the procedure described in the synthesis of 52.4. MS (ES): m/z193.14 [M+H]⁺.

Synthesis of compound 54.4. Compound 54.4 was prepared from 54.3following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 192.15 [M+H]⁺.

Synthesis of compound I-54. Compound I-54 was prepared from 54.4 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by preparative HPLC. MS (ES): m/z: 473.39 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 8.63 (s, 1H), 8.50 (s, 1H),8.16-8.14 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.65 (s, 1H), 7.57-7.55 (d,J=8.4 Hz, 1H), 7.36 (s, 1H), 6.92-6.90 (d, J=7.6 Hz, 1H), 6.62-6.61 (d,J=3.6 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 2.03 (s, 3H).

Example 55:N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-55. Compound I-55 was prepared from 54.4 andInt-4 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2% methanol in dichloromethane as eluant). MS (ES): m/z:498.76 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.62 (s, 1H), 8.80 (s, 1H),8.56 (s, 1H), 8.23-8.22 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 7.92-7.90 (d,J=8.4 Hz, 1H), 7.70 (s, 1H), 7.14-7.12 (d, J=8.4 Hz, 1H), 6.72-6.71 (m,1H), 3.96 (s, 3H), 3.65 (s, 3H), 2.04 (s, 3H).

Example 56:N-(4-((2-((1-((1s,3s)-3-methoxycyclobutyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 56.2. To a solution of 56.1 (10 g, 56.75 mmol, 1.0equiv) in methanol (100 mL) was added sodium borohydride (6.4 g, 170.2mmol, 3.0 equiv) in small portions at 0° C. The reaction mixture wasstirred at room temperature for 3 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 56.2. MS (ES): m/z179.3 [M+H]⁺.

Synthesis of compound 56.3. To a solution of 56.2 (9.2 g, 51.62 mmol,1.0 equiv) in THF (100 mL) was added sodium hydride (3.71 g, 77.43 mmol,1.5 equiv) at 0° C. and stirred for 30 min. Methyl iodide (8.73 g, 61.94mmol, 1.2 equiv) was added. The reaction mixture was stirred at roomtemperature for 3 h. It was poured over ice, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 56.3. MS (ES): m/z 193.3 [M+H]⁺.

Synthesis of compound 56.4. A flask charged with compound 56.3 (8.1 g,42.13 mmol, 1.0 equiv), 10% palladium on carbon (4.0 g) and methanol (80mL) was vacuumed and purged with hydrogen three times. The mixture wasstirred at rt under 1 atm hydrogen atmosphere for 1 h. The flask wasvacuumed and purged with nitrogen three times before it was opened toair. The reaction mixture was filtered through a pad of Celite® andrinsed with methanol. The filtrate was concentrated under reducedpressure and the residue was purified by flash column chromatography onsilica gel (CombiFlash®, 5% methanol in dichloromethane as eluant) toafford 56.4. MS (ES): m/z 103.2 [M+H]⁺.

Synthesis of compound 56.6. To a solution of compound 56.4 (3.4 g, 33.29mmol, 1.0 equiv), 4-nitrobenzoic acid (56.5, 5.56 g, 33.29 mmol, 1.0equiv) and triphenyl phosphine (10.46 g, 39.94 mmol, 1.2 equiv) indichloromethane (40 mL) was added diisopropyl azodicarboxylate (8.067 g,39.94 mmol, 1.2 equiv) 0° C. The reaction mixture was stirred at roomtemperature for 4 h. It poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20% ethyl acetate in hexane as eluant) toafford 56.6. MS (ES): m/z 252.24 [M+H]⁺.

Synthesis of compound 56.7. To a solution of 56.6 (3.9 g, 15.52 mmol,1.0 equiv) in methanol (40 mL) and water (8 mL) was added potassiumcarbonate (4.28 g, 31.04 mmol, 2.0 equiv). The reaction mixture wasstirred at room temperature for 3 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 56.7. MS (ES): m/z103.3 [M+H]⁺.

Synthesis of compound 56.8. To a solution of 56.7 (1.1 g, 10.77 mmol,1.0 equiv) in dichloromethane (10 mL) was added triethylamine (1.95 mL,14.0 mmol, 1.3 equiv) at 0° C. followed by addition of methanesulfonylchloride (1.59 g, 14.0 mmol, 1.3 equiv). The reaction mixture wasstirred at room temperature for 2 h. It was poured over ice-water,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 10% ethylacetate in hexane as eluant) to afford 56.8. MS (ES): m/z 181.2 [M+H]⁺.

Synthesis of compound 56.10. A mixture of 56.9 (0.2 g, 0.961 mmol, 1.0equiv) and 56.8 (0.207 g, 1.15 mmol, 1.2 equiv) and cesium carbonate(0.468 g, 1.44 mmol, 1.5 equiv) in THF (7 mL) was heated to reflux for72 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 15% ethyl acetate in hexane as eluant) toafford 56.10. MS (ES): m/z 293.2 [M+H]⁺.

Synthesis of compound 56.11. Compound 56.11 was prepared from 56.10following the procedure described in the synthesis of Int-2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 263.2 [M+H]⁺.

Synthesis of compound 56.12. Compound 56.12 was prepared from 56.11following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 305.3 [M+H]⁺.

Synthesis of compound I-56. Compound I-56 was prepared from 56.12 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.5% methanol in dichloromethane as eluant). MS (ES): m/z:540.8 [M−H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 8.95 (s, 1H),8.80 (s, 1H), 8.38 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.64 (s, 1H),7.38-7.36 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 6.86-6.84 (d, J=8.0 Hz, 1H),6.63-6.62 (d, J=5.2 Hz, 1H), 4.80-4.76 (m, 1H), 3.86-3.82 (m, 1H), 3.67(s, 3H), 3.24 (s, 3H), 2.86 (bs, 2H),2.13-2.11 (m, 2H), 2.03 (s, 3H).

Example 57:N-(4-((2-((1-((1s,3s)-3-methoxycyclobutyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)amino)-1,7-dimethyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-57. Compound I-57 was prepared from 56.12 andInt-3 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3-4% methanol in dichloromethane as eluant). MS (ES): m/z:557.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 8.85 (s, 1H),8.78 (s, 1H), 8.35 (s, 1H), 8.15-8.13 (d, J=5.2 Hz, 1H), 7.58 (s, 1H),7.22-7.20 (d, J=8 Hz, 1H), 6.82-6.80 (d, J=8.4 Hz, 1H), 6.55 (bs, 1H),4.80-4.76 (m, 1H), 3.89 (s, 3H), 3.85-3.82 (m, 1H), 3.23 (s, 3H),3.18-3.17 (d, 1H), 2.87 (bs, 2H), 2.43 (s, 3H), 2.12-2.10 (m, 1H), 2.03(s, 3H).

Example 58:(R)—N-(4-((2-((1-(1,4-dioxan-2-yl)methyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((1-((1,4-dioxan-2-yl)methyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-58.2. A mixture of 58.1 (5.0 g, 48.96 mmol,1.0 equiv), sodium bicarbonate (12.337 g, 146.88 mmol, 3.0 equiv) andiodine (37.3 g, 146.88 mmol, 3.0 equiv) in acetonitrile (25 mL) wasstirred at room temperature for 16 h. It was poured over crushed ice,stirred and extracted with ethyl acetate. The combined organic layerswere washed with aqueous sodium thiosulphate followed by brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 15% ethyl acetate in hexane as eluant) toafford (±)-58.2. MS (ES): m/z 229.10 [M+H]⁺.

Synthesis of compound (±)-58.3. To a solution of 52.1 (2.25 g, 10.81mmol, 1.0 equiv) in DMF (25 mL) was added potassium carbonate (2.98 g,21.62 mmol, 2.0 equiv) and stirred for 15 min. To the mixture was added(±)-58.2 (2.96 g, 12.97 mmol, 1.2 equiv). The reaction mixture wasstirred at 80° C. for 16 h. It was poured over ice-water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexaneas eluant) to afford (±)-58.3. MS (ES): m/z 309.2 [M+H]⁺.

Synthesis of compound (±)-58.4. A mixture of compound (±)-58.3 (1.2 g,3.89 mmol, 1.0 equiv), 10% palladium on carbon (0.6 g) in methanol (10mL) and THF (4 mL) was vacuumed and purged with hydrogen. It was stirredat rt under 1 atm of hydrogen for 1 h. It was filtered through a pad ofCelite® and rinsed with methanol. The filtrate was concentrated underreduced pressure to obtain (±)-58.4. MS (ES): m/z 279.3 [M+H]⁺.

Synthesis of compound (±)-58.5. Compound (±)-58.5 was prepared from(±)-58.4 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 321.3 [M+H]⁺.

Synthesis of compound (±)-I-58. Compound (±)-I-58 was prepared from(±)-58.5 and Int-2 following the procedure described in the synthesis ofI-1. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2% methanol in dichloromethane as eluant). MS (ES):m/z: 559.8 [M+H]⁺.

I-58-a and I-58-b. Enantiomers of 1-58 were separated on SFC (column:CHIRALCEL OJ-H (250 mm×4.6 mm, 5 μm); eluent: 0.1% DEA in IPA:ACN(50:50); flow rate=4 mL/min) to get first eluting fraction (I-58-a) andsecond eluting fraction (I-58-b). (*Absolute stereochemistry notdetermined.)

I-58-a. MS (ES): m/z: 559.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.65-8.64 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.16-8.14 (d, J=5.6Hz, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=8.4 Hz, 1H), 7.37(bs, 1H), 6.92 (m, 1H), 6.63-6.61 (m, 1H), 4.23-4.19 (m, 1H), 4.13-4.08(m, 1H), 3.93 (bs, 1H), 3.82-3.76 (m, 4H), 3.66-3.64 (m, 2H), 3.48 (s,3H), 2.02 (s, 3H).

I-58-b. MS (ES): m/z: 559.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.65-8.64 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.16-8.14 (d, J=5.6Hz, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=8.4 Hz, 1H), 7.37(bs, 1H), 6.92 (m, 1H), 6.63-6.61 (m, 1H), 4.23-4.19 (m, 1H), 4.13-4.08(m, 1H), 3.93 (bs, 1H), 3.82-3.76 (m, 4H), 3.66-3.64 (m, 2H), 3.48 (s,3H), 2.02 (s, 3H).

Example 59:N-(4-((2-((1-((3R,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((1-((3S,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 59.2. To a solution of 59.1 (10 g, 118.8 mmol, 1.0equiv) in dichloromethane (100 mL) was added m-chloroperbenzoic acid(22.5 g, 130.68 mmol, 1.1 equiv) portion-wise at 0° C. The reactionmixture was stirred at room temperature for 18 h. It was poured into asaturated aqueous solution of sodium bicarbonate and stirred for a fewminutes. The organic layer was separated washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 59.2. ¹H NMR (DMSO-d6, 400 MHz): δ 3.84 (dd, J=2.7Hz, 13.4 Hz, 1H), 3.74-3.70 (m, 1H), 3.38-3.26 (m, 3H), 3.10-3.09 (m,1H), 1.87-1.82 (m, 2H).

Synthesis of compound trans-(±)-59.3 and trans-(±)-59.4. A mixture of59.2 (2.5 g, 12.01 mmol, 1.0 equiv), 52.1 (6.01 g, 60.07 mmol, 5.0equiv) and potassium carbonate (4.143 g, 30.02 mmol, 2.5 equiv) in DMFwas stirred at 120° C. for 16 h. The reaction mixture was cooled to roomtemperature, poured into ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gelfollowed by preparative HPLC to obtain trans-(±)-59.3. MS (ES): m/z309.2 [M+H]⁺ and trans-(±)-59.4. MS (ES): m/z 309.3 [M+H]⁺.

Synthesis of compound trans-(±)-59.5. To a solution of trans-(±)-59.3(0.135 g, 0.438 mmol, 1.0 equiv) in DMF (1 mL) was added sodium hydride(0.042 g, 0.876 mmol, 2.0 equiv) at 0° C. The reaction mixture wasstirred for 30 min and was added methyl iodide (0.168 g, 0.876 mmol, 2.0equiv). It was stirred at room temperature for 1 h before it was pouredover ice, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to obtaintrans-(±)-59.5. MS (ES): m/z 323.2 [M+H]⁺.

Synthesis of compound trans-(±)-59.6. Compound trans-(±)-59.6 wasprepared from trans-(±)-59.5 following the procedure described in thesynthesis of 52.4. The crude product was used in the next step withoutfurther purification. MS (ES): m/z 293.3 [M+H]⁺.

Synthesis of compound trans-(±)-59.7. Compound trans-(±)-59.7 wasprepared from trans-(±)-59.6 following the procedure described in thesynthesis of 1.2. The crude product was used in the next step withoutfurther purification. MS (ES): m/z 335.3 [M+H]⁺.

Synthesis of compound trans-(±)-I-59. Compound trans-(±)-I-59 wasprepared from trans-(±)-I-57 and Int-2 following the procedure describedin the synthesis of 1-2. MS (ES): m/z: 573.8 [M+I-1]⁺.

I-59-a and I-59-b. trans-(±)-I-59 was separated on HPLC (CHIRALCEL OX-H(250 mm×21.0 mm, 5 μm), mobile phases: (A) 0.1% diethylamine in Hexane(B) 0.1% diethylamine in isopropanol/acetonitrile (70:30); flow rate:19mL/min) to get first eluting fraction (I-59-a) and second elutingfraction (I-59-b). (*Absolute stereochemistry not determined.)

I-59-a: MS (ES): m/z: 573.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 8.07(s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=8.4 Hz, 1H), 7.38 (s, 1H),6.92-6.90 (d, J=8.4 Hz, 1H), 6.63-6.62 (d, J=3.2 Hz, 1H), 4.83 (bs, 1H),4.13 (bs, 1H), 3.97-3.88 (m, 2H), 3.74 (s, 3H), 3.58-3.52 (m, 1H), 3.21(s, 3H), 2.33-2.26 (m, 1H), 2.02 (s, 3H), 1.54-1.51 (m, 2H).

I-59-b: MS (ES): m/z: 573.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 8.07(s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=8.4 Hz, 1H), 7.37 (s, 1H),6.92-6.90 (d, J=8.4 Hz, 1H), 6.63-6.62 (d, J=3.2 Hz, 1H), 4.83 (bs, 1H),4.13 (bs, 1H), 3.97-3.88 (m, 2H), 3.74 (s, 3H), 3.58-3.52 (m, 1H), 3.21(s, 3H), 2.33-2.26 (m, 1H), 2.02 (s, 3H), 1.54-1.51 (m, 2H).

Example 60:N-(4-((2-((1-((3R,4S)-4-methoxytetrahydro-2H-pyran-3-yl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((1-((3S,4R)-4-methoxytetrahydro-2H-pyran-3-yl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 60.1. Compound 60.1 was prepared from 52.1following the procedure described in the synthesis of 52.4. The crudeproduct was used in the next step without further purification. MS (ES):m/z 179.1 [M+H]⁺.

Synthesis of compound 60.2. To a solution of 60.1 (6.5 g, 36.49 mmol,1.0 equiv) in toluene (25 mL) was added acetic anhydride (17 mL, 182.45mmol, 5.0 equiv). The reaction mixture was heated to reflux for 2 h. Itwas concentrated under reduced pressure. The residue was furtherpurified by trituration with diethyl ether to obtain 60.2. MS (ES): m/z221.3 [M+H]⁺.

Synthesis of compound (±)-60.4. To a mixture of 60.3 (5.0 g, 49.94 mmol,1.0 equiv) and ammonium acetate (0.384 g, 4.99 mmol, 0.1 equiv) indiethyl ether (50 mL) at 0° C. was added N-bromosuccinimide (9.28 g,52.43 mmol, 1.05 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was filtered through a pad of Celite® and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 10%ethyl acetate in hexane as eluant) to afford (±)-60.4. MS (ES): m/z180.1 [M+H]⁺.

Synthesis of compound (±)-60.5. To a solution of (±)-60.4 (4.6 g, 25.7mmol, 1.0 equiv) and 60.2 (5.66 g, 25.7 mmol, 1.0 equiv) in DMF (50 mL)was added potassium carbonate (5.67 g, 41.12 mmol, 1.6 equiv) andstirred at room temperature for 12 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 40% ethylacetate in hexane as eluant) to afford (±)-60.5. MS (ES): m/z 319.1[M+H]⁺.

Synthesis of compound (±)-60.6. To a solution of (±)-60.5 (2.5 g, 7.86mmol, 1.0 equiv) in methanol (25 mL) was added sodium borohydride (0.348g, 9.43 mmol, 1.2 equiv) in small portions at 0° C. and stirred for 30min. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 60% ethyl acetate in hexane as eluant) toafford (±)-60.6. MS (ES): m/z 321.3 [M+H]⁺.

Synthesis of compound (±)-60.7. To a solution of (±)-60.6 (1.2 g, 3.75mmol, 1.0 equiv) in dichloromethane (7.5 mL) and water (2.5 mL) wasadded silver oxide (4.33 g, 18.75 mmol, 5.0 equiv) and stirred at roomtemperature for 15 min. To the mixture was added methyl iodide (0.798 g,5.62 mmol, 1.5 equiv). The reaction mixture was stirred at roomtemperature for 72 h. It was poured over ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 30% ethyl acetate inhexane as eluant) to afford (±)-60.7. MS (ES): m/z 335.3 [M+H]⁺.

Synthesis of compound (±)-60.8. A mixture of (±)-60.7 (0.680 g, 2.03mmol, 1.0 equiv) and potassium carbonate (5.6 g, 40.6 mmol, 20 equiv) inmethanol (10 mL) was heated to reflux for 16 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to obtain(±)-60.8. MS (ES): m/z 293.3 [M+H]⁺.

Synthesis of compound (±)-60.9. Compound (±)-60.9 was prepared from(±)-60.8 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 335.3 [M+H]⁺.

Synthesis of compound (±)-I-60. Compound (±)-I-60 was prepared from(±)-60.9 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES): m/z:573.5 [M+H]⁺.

I-60-a and I-60-b. Compound (±)-I-60 was separated on HPLC (column:CHIRALPAK IC (250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% DEA inn-hexane (B) 0.1% DEA in 2-propanol:acetonitrile (70:30); flow rate: 20mL/min) to get first eluting fraction (I-60-a) and second elutingfraction (I-60-b). (*Absolute stereochemistry not determined.)

I-60-a. MS (ES): m/z: 573.7 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 8.07(s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=9.2 Hz, 1H), 7.38 (s, 1H),6.93-6.91 (d, J=8.4 Hz, 1H), 6.63-6.62 (m, 1H), 5.76 (s, 1H), 4.83 (bs,1H), 4.13 (bs, 1H), 3.97-3.87 (m, 2H), 3.73 (s, 3H), 3.58-3.52 (m, 1H),3.21 (s, 3H), 2.33-2.26 (m, 1H), 2.02 (s, 3H), 1.54-1.51 (m, 1H).

I-60-b. MS (ES): m/z: 573.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 8.07(s, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J=8.4 Hz, 1H), 7.38 (s, 1H),6.93-6.91 (d, J=8.4 Hz, 1H), 6.62 (bs, 1H), 5.76 (s, 1H), 4.83 (bs, 1H),4.13 (bs, 1H), 3.94-3.88 (m, 2H), 3.74 (s, 3H), 3.55-3.53 (m, 1H), 3.21(s, 3H), 2.33-2.26 (m, 1H), 2.02 (s, 3H), 1.51 (bs, 1H).

Example 61:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 61.2. To a solution of 61.1 (5.0 g, 22.83 mmol,1.0 equiv) in DMF (50 mL) was added potassium carbonate (6.6 g, 47.94mmol, 2.1 equiv) and stirred for 15 min. To the mixture was added methyliodide (3.56 g, 25.11 mmol, 1.1 equiv). The reaction mixture was stirredat room temperature for 1 h. It was poured over ice-water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 61.2. MS (ES): m/z 234.02 [M+H]⁺.

Synthesis of compound 61.3. A mixture of 61.2 (0.7 g, 3.0 mmol, 1.0equiv), cyclopropylboronic acid (0.774 g, 9.0 mmol, 3.0 equiv),potassium phosphate (1.9 g, 9.0 mmol, 3.0 equiv) andtricyclohexylphosphine (0.168 g, 0.6 mmol, 0.2 equiv) in toluene (10 mL)and water (1 mL) was degassed by bubbling argon for 10 min.Palladium(II) acetate (0.336 g, 1.5 mmol, 0.5 equiv) was added underargon, and degassed again for 5 min. The reaction mixture was stirred at100° C. for 2 h. It was cooled to room temperature, filtered through apad of Celite®. The filtrate was poured over water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 30% ethyl acetate in hexane as eluant) toafford 61.3. MS (ES): m/z 195.2 [M+H]⁺.

Synthesis of compound 61.4. Compound 61.4 was prepared from 61.3following the procedure described in the synthesis of 52.4. The crudeproduct was used in the next step without further purification. MS (ES):m/z 165.21 [M+H]⁺.

Synthesis of compound 61.5. Compound 61.5 was prepared from 61.4following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 207.3 [M+H]⁺.

Synthesis of compound I-61. Compound I-61 was prepared from 61.5 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by preparative HPLC. MS (ES): m/z: 445.31 [M−H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 8.32-8.31 (d, J=1.6 Hz, 1H),8.21 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.52-7.50 (d,J=8.4 Hz, 1H), 7.33-7.32 (d, J=1.6 Hz, 1H), 7.14 (s, 1H), 6.90-6.87 (m,1H), 6.63-6.61 (m, 1H), 3.69 (s, 3H), 3.54 (s, 3H), 2.02 (s, 3H),1.82-1.77 (m, 1H), 0.88-0.83 (m, 2H), 0.59-0.58 (m, 2H).

Example 62:N-(4-((7-cyano-2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-62. Compound I-62 was prepared from 61.5 andInt-2 following the procedure described in the synthesis of I-1. Theresidue was purified by preparative HPLC. MS (ES): m/z: 470.75 [M+H]⁺, HNMR (DMSO-d6, 400 MHz): δ 10.61 (s, 1H), 8.47 (s, 1H), 8.25-8.22 (m,2H), 7.85-7.83 (d, J=8.4 Hz, 1H), 7.69 (s, 1H), 7.20 (s, 1H), 7.11-7.09(d, J=8.4 Hz, 1H), 6.72-6.71 (d, J=3.2 Hz, 1H), 3.93 (s, 3H), 3.55 (s,3H), 2.04 (s, 3H), 1.80 (bs, 1H), 0.86-0.85 (m, 2H), 0.59-0.58 (m, 2H).

Example 63:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-63. Compound I-63 was prepared from 61.5 and Int-4following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,1.7% methanol in dichloromethane as eluant). MS (ES): m/z: 446.96[M+H]⁺, ¹H NMR (CDCl₃, 400 MHz): δ 8.46-8.45 (d, J=2 Hz, 1H), 8.27 (bs,1H), 8.16-8.14 (d, J=6 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.90-7.88(d, J=8 Hz, 1H), 6.87-6.85 (d, J=8 Hz, 1H), 6.79-6.77 (m, 2H), 3.73 (s,3H), 3.65 (s, 3H), 2.20 (s, 3H), 1.85-1.79 (m, 1H), 0.95-0.90 (m, 2H),0.70-0.66 (m, 2H).

Example 64:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-3,7-dimethyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 64.2 To a solution of2-chloro-4-methyl-5-nitropyridine (64.1, 3.0 g, 17.38 mmol, 1.0 equiv)and urea hydrogen peroxide (3.43 g, 36.49 mmol, 2.1 equiv) indichloromethane (30 mL) at 0° C. was added trifluoroacetic anhydride(4.8 mL, 34.76 mmol, 2.0 equiv) dropwise. The reaction mixture wasstirred at room temperature for 3 h. It was poured over ice-water andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain residue. The residue wasdissolved in phosphorousoxy chloride (15 mL) and stirred at 80° C. for12 h under nitrogen. It was poured over crushed ice, stirred andextracted with dichloromethane. The combined organic layers were washedwith saturated sodium bicarbonate solution followed by brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 64.2. MS (ES): m/z 208.1 [M+H]⁺.

Synthesis of compound 64.3. Compound 64.3 was prepared from 64.2following the procedure described in the synthesis of Int-2.2. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2% ethyl acetate in hexane as eluant). MS (ES): m/z 202.6[M+H]⁺.

Synthesis of compound 64.4. To a solution of 64.3 (0.150 g, 0.744 mmol,1.0 equiv) in N, N-dimethylformamide (1.5 mL) was added Int-1 (0.113 g,0.744 mmol, 1.0 equiv) followed by sodium carbonate (0.118 g, 1.116mmol, 1.5 equiv). The reaction mixture was stirred at 90° C. for 12 hunder nitrogen. It was cooled to room temperature, poured over ice-waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 40% ethyl acetate inhexane) to afford 64.4. MS (ES): m/z 318.3 [M+H]⁺.

Synthesis of compound 64.5. Compound 64.5 was prepared from 64.4following the procedure described in the synthesis of Int-2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 288.3 [M+H]⁺.

Synthesis of compound I-64. Compound I-64 was prepared from compound64.5 and compound 61.5 following the procedure described in thesynthesis of I-1. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5% methanol indichloromethane as eluant). MS (ES): m/z: 460.40 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.55 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H),8.20-8.19 (d, J=5.2 Hz, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 6.80 (s, 1H),6.73 (bs, 1H), 3.62 (s, 3H), 3.54 (s, 3H), 2.55 (s, 3H), 2.05 (s, 3H),1.80 (bs, 1H), 0.88-0.87 (d, 2H), 0.60 (bs, 2H).

Example 65:N-(4-((2-((5-cyclopropyl-1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 65.1. To a solution of 61.1 (5.0 g, 22.83 mmol,1.0 equiv) in DMF (50 mL) was added potassium carbonate (6.6 g, 47.94mmol, 2.1 equiv) and stirred for 15 min. To the mixture was addedisopropyl bromide (3.36 g, 27.39 mmol, 1.2 equiv). The reaction mixturewas stirred at 85° C. for 16 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 7-8% ethyl acetate inhexane as eluant) to afford 65.1. MS (ES): m/z 262.2 [M+H]⁺.

Synthesis of compound 65.2. Compound 65.2 was prepared from 65.1following the procedure described in the synthesis of 61.3. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,20% ethyl acetate in hexane as eluant). MS (ES): m/z 223.3 [M+H]⁺.

Synthesis of compound 65.3. Compound 65.3 was prepared from 65.2following the procedure described in the synthesis of 52.4. The crudeproduct was used in the next step without further purification. MS (ES):m/z 193.3 [M+H]⁺.

Synthesis of compound 65.4. Compound 65.4 was prepared from 65.3following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 235.3 [M+H]⁺.

Synthesis of compound I-65. Compound I-65 was prepared from 65.4following the procedure described in the synthesis of I-1. The residuewas purified by preparative HPLC. MS (ES): m/z: 474.40 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.57 (s, 1H), 8.37 (s, 1H), 8.26-8.25 (d, J=1.6Hz, 1H), 8.22-8.21 (d, J=5.6 Hz, 1H), 7.98-7.96 (d, J=8.4 Hz, 1H), 7.78(s, 1H), 7.20 (s, 1H), 6.93-6.91 (d, J=8.4 Hz, 1H), 6.77-6.75 (m, 1H),5.18-5.14 (m, 1H), 3.65 (s, 3H), 2.06 (s, 3H), 1.90-1.86 (m, 1H), 1.36(s, 6H), 0.91-0.87 (m, 2H), 0.65-0.61 (m, 2H).

Example 66:(R)—N-(4-((2-((5-cyclopropyl-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-cyclopropyl-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-66.3. To a solution of 66.1 (1.5 g, 6.85 mmol,1.0 equiv) in DMF (15 mL) was added potassium carbonate (1.89 g, 13.7mmol, 2.0 equiv) and stirred for 15 min. To the mixture was added3-(bromomethyl)tetrahydrofuran ((±)-66.2, 1.36 g, 8.22 mmol, 1.2 equiv).The reaction mixture was stirred at 90° C. for 6 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 50% ethylacetate in hexane as eluant) to afford (±)-66.3. MS (ES): m/z 304.1[M+H]⁺.

Synthesis of compound (±)-66.4. Compound (±)-66.4 was prepared from(±)-66.3 following the procedure described in the synthesis of 61.3. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5% methanol in dichloromethane as eluant). MS (ES): m/z265.2 [M+H]⁺.

Synthesis of compound (±)-66.5. Compound (±)-66.5 was prepared from(±)-66.4 following the procedure described in the synthesis of 52.4. Thecrude product was used in the next step without further purification. MS(ES): m/z 235.3 [M+H]⁺.

Synthesis of compound (±)-66.6. Compound (±)-66.6 was prepared from(±)-66.5 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 277.3 [M+H]⁺.

Synthesis of compound (±)-I-66. Compound (±)-I-66 was prepared from(±)-66.6 following the procedure described in the synthesis of I-1. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3% methanol in dichloromethane as eluant). MS (ES): m/z:515.5 [M+H]⁺.

I-66-a and I-66-b. (±)-I-66 was separated on SFC (column: CHIRALCEL OJ-H(250 mm×4.6 mm, 5 μm); mobile phase: 0.1% DEA in MeOH; flow rate: 4mL/min) to get first eluting fraction (I-66-a) and second elutingfraction (I-66-b). (*Absolute stereochemistry not determined.)

I-66-a. MS (ES): m/z: 515.3 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.33-8.32 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.16-8.15 (d, J=5.6Hz, 1H), 7.66 (s, 1H), 7.53-7.51 (d, J=8.4 Hz, 1H), 7.34 (bs, 1H), 7.18(s, 1H), 6.91-6.88 (m, 1H), 6.64-6.62 (m, 1H), 4.00-3.99 (m, 2H),3.85-3.80 (m, 1H), 3.70 (s, 3H), 3.67-3.62 (m, 2H), 3.53-3.50 (m, 1H),2.78-2.75 (m, 1H), 2.03 (s, 3H), 1.94-1.81 (m, 2H), 1.70-1.62 (m, 1H),0.95-0.93 (m, 2H), 0.62-0.61 (m, 2H).

I-66-b. MS (ES): m/z: 515.3 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.33-8.32 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.16-8.15 (d, J=5.6Hz, 1H), 7.66 (s, 1H), 7.53-7.51 (d, J=8.4 Hz, 1H), 7.34 (bs, 1H), 7.18(s, 1H), 6.91-6.88 (m, 1H), 6.64-6.62 (m, 1H), 4.00-3.99 (m, 2H),3.85-3.80 (m, 1H), 3.70 (s, 3H), 3.67-3.62 (m, 2H), 3.53-3.50 (m, 1H),2.78-2.75 (m, 1H), 2.03 (s, 3H), 1.94-1.81 (m, 2H), 1.70-1.62 (m, 1H),0.95-0.93 (m, 2H), 0.62-0.61 (m, 2H).

Example 67:(R)—N-(4-((2-((5-cyclopropyl-2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-cyclopropyl-2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 67.2. To a solution of 67.1 (20 g, 238 mmol, 1.0equiv) in dichloromethane (200 mL) was added bromine (12.2 mL, 238 mmol,1.0 equiv) in dichloromethane (100 mL) at −78° C. dropwise. The reactionmixture was stirred at −78° C. for 2 h, then it was allowed to warm toroom temperature stirred for 16 h. To the mixture was added dropwisetriethylamine (66 mL, 476 mmol, 2.0 equiv) in dichloromethane (100 mL).It was stirred for 5 h. The reaction mixture was concentrated underreduced pressure. To the residue was added diethyl ether. Solids wasremoved by filtration. The filtrate was concentrated under reducedpressure. The crude product was purified by vacuum distillation (80° C.,0.02 mm Hg) to obtained pure compound 67.2. ¹H NMR (400 M Hz, CDCl₃):6.68 (s, 1H), 4.02-4.00 (t, J=4 Hz, 2H), 2.45-2.42 (m, 2H), 2.06-2.00(m, 2H).

Synthesis of compound 67.4. To a solution of 67.2 (8 g, 49.08 mmol, 1.0equiv) and 67.3 (6.48 g, 58.89 mmol, 1.2 equiv) in 1,4-dioxane (100 mL)was added potassium carbonate (13.6 g, 98.16 mmol, 2.0 equiv) anddegassed by bubbling argon through for 15 min. Copper iodide (1.4 g,7.40 mmol, 0.15 equiv) and 1,2-dimethylethylenediamine (1.60 mL, 14.72mmol, 0.30 equiv) was added. The reaction mixture again degassed withargon for 5 min. It was stirred at 110° C. for 12 h under argon. It wascooled to room temperature, poured over water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1.2% methanol in dichloromethane to obtain67.4. MS (ES): m/z 193.09 [M+H]⁺.

Synthesis of compound (±)-67.5. A mixture of 67.4 (8 g, 41.62 mmol, 1.0equiv) and palladium on charcoal (4 g) in methanol (100 mL) was stirredat rt under 1 atm hydrogen for 16 h. It was filtered through a pad ofCelite® and rinsed with methanol. The filtrate was concentrated underreduced pressure. The residue was purified by trituration with n-pentaneto obtain (±)-67.5. MS (ES): m/z 195.11 [M+H]⁺.

Synthesis of compound (±)-67.6. To a solution of (±)-67.5 (2 g, 10.30mmol, 1.0 equiv) in dichloromethane (20 mL) at 0° C. was addedtriethylamine (4.33 mL, 30.9 mmol, 3.0 equiv) and acetic anhydride (1.55mL, 16.49 mmol, 1.6 equiv). The reaction mixture was stirred at roomtemperature for 2 h. It was poured over water and extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 0-5% methanol in dichloromethane) to afford (±)-67.6. MS(ES): m/z 237.12 [M+H]⁺.

Synthesis of compound (±)-67.7. To a solution of (±)-67.6 (0.9 g, 3.81mmol, 1.0 equiv) in DMF (10 mL) was added N-bromosuccinimide (1.017 g,5.71 mmol, 1.5 equiv) and stirred at room temperature for 1 h. It waspoured over ice-water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,60% ethyl acetate in hexane as eluant) to afford (±)-67.7. MS (ES): m/z316.2 [M+H]⁺.

Synthesis of compound (±)-67.8. Compound (±)-67.8 was prepared from(±)-67.7 following the procedure described in the synthesis of 61.3. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, ethyl acetate as eluant). MS (ES): m/z 277.3 [M+H]⁺.

Synthesis of compound (±)-67.9. To a solution of compound (±)-67.8(0.182 g, 0.658 mmol, 1.0 equiv) in methanol (10 mL) was added potassiumcarbonate (1.816 g, 13.16 mmol, 20.0 equiv). The reaction mixture washeated to reflux for 16 h. It was poured over water, extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2.0% methanol in dichloromethane as eluant) toafford (±)-67.9. MS (ES): m/z 235.3 [M+H]⁺.

Synthesis of compound (±)-67.10. Compound (±)-67.10 was prepared from(±)-67.9 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 277.4 [M+H]⁺.

Synthesis of compound (±)-I-67. Compound (±)-I-67 was prepared from(±)-67.10 and Int-2 following the procedure described in the synthesisof IA. The product was purified by flash column chromatography on silicagel (CombiFlash®, 1.2% methanol in dichloromethane as eluant). MS (ES):m/z: 515.4 [M+H]⁺.

I-67-a and I-67-b. (±)-I-67 was separated on HPLC (column: CHIRALPAK IH(250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane(B) 0.1% diethylamine in 2-propanol:acetonitrile (70:30); flow rate: 20mL/min) to afford first eluting fraction (I-67-a) and second elutingfraction (I-67-b). (*Absolute stereochemistry not determined.)

I-67-a. MS (ES): m/z: 515.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.26-8.25 (d, J=3.2 Hz, 2H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.64(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (bs, 1H), 7.22 (s, 1H),6.89-6.87 (m, 1H), 6.63-6.61 (m, 1H), 4.97 (bs, 1H), 3.85-3.80 (m, 2H),3.69 (s, 3H), 3.50-3.45 (m, 1H), 2.18-2.12 (m, 1H), 2.08 (s, 3H),1.93-1.83 (m, 4H), 1.23 (bs, 1H), 1.07-1.03 (m, 2H), 0.67 (bs, 2H).

I-67-b. MS (ES): m/z: 515.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.25 (bs, 2H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.64 (s, 1H),7.52-7.50 (d, J=8.4 Hz, 1H), 7.34 (bs, 1H), 7.24 (s, 1H), 6.90-6.88 (d,J=7.6 Hz, 1H), 6.63-6.62 (d, J=3.6 Hz, 1H), 4.86 (bs, 1H), 3.85-3.80 (m,2H), 3.69 (s, 3H), 3.50-3.45 (m, 1H), 2.14-2.12 (m, 1H), 2.08 (s, 3H),1.93-1.77 (m, 4H), 1.23 (bs, 1H), 0.88-0.86 (m, 2H), 0.62-0.61 (bs, 2H).

Example 68:(R)—N-(4-((2-((5-cyclopropyl-2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-cyclopropyl-2-oxo-1-(tetrahydro-2H-pyran-3-yl)-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-I-68. Compound (±)-I-68 was prepared from(±)-67.10 and Int-4 following the procedure described in the synthesisof I-1. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 4.1% methanol in dichloromethane as eluant). MS(ES): m/z: 516.41 [M+H]⁺.

I-68-a and I-68-b. (±)-I-68 were separated on HPLC (column CHIRALPAK IC(250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% diethylamine in n-hexane(B) 0.1% diethylamine in 2-propanol:acetonitrile (70:30); flow rate: 20mL/min) to afford first eluting fraction (I-68-a) and second elutingfraction (I-68-b). (*Absolute stereochemistry not determined.)

I-68-a. MS (ES): m/z: 516.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.57(s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.21-8.20 (d, J=4.4 Hz, 1H),7.99-7.96 (m, 1H), 7.78 (bs, 1H), 7.26 (bs, 1H), 6.94-6.91 (m, 1H), 6.76(bs, 1H), 4.86 (bs, 1H), 3.82 (bs, 2H), 3.65 (s, 3H), 3.48 (bs, 2H),3.19-3.17 (m, 1H), 2.06 (s, 3H), 1.93-1.77 (m, 4H), 0.88-0.86 (m, 2H),0.63 (bs, 2H).

I-68-b. MS (ES): m/z: 516.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.57(s, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 8.22-8.21 (d, J=4.4 Hz, 1H),7.98-7.96 (d, J=8.0 Hz, 1H), 7.78 (bs, 1H), 7.27 (bs, 1H), 6.93-6.91 (d,J=8.4 Hz, 1H), 6.76-6.75 (d, J=3.6 Hz, 1H), 4.87 (bs, 1H), 3.83 (bs,2H), 3.65 (s, 3H), 3.48 (bs, 2H), 3.18-3.17 (m, 1H), 2.06 (s, 3H), 1.94(bs, 1H), 1.86 (bs, 1H), 1.77-1.73 (m, 2H), 0.89-0.87 (m, 2H), 0.63-0.62(m, 2H).

Example 69:N-(4-((2-((5-cyclopropyl-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 69.3. To a solution of 69.1 (3 g, 14.28 mmol, 1.0equiv) and 69.2 (2.4 g, 17.14 mmol, 1.2 equiv) in dioxane (30 mL) wasadded copper acetate (2.60 g, 14.28 mmol, 1.0 equiv) and triethylamine(5.0 mL, 35.7 mmol, 2.5 equiv) under nitrogen. The reaction was stirredat 80° C. for 5 h. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,10% ethyl acetate in hexane to obtain 69.3. MS (ES): m/z 222.20 [M+H]⁺.

Synthesis of compound 69.4. Compound 69.4 was prepared from 69.3following the procedure described in the synthesis of 52.4. The crudeproduct was used in the next step without further purification. MS (ES):m/z 195.23 [M+H]⁺.

Synthesis of compound 69.5. To a solution of 69.4 (0.500 g, 2.57 mmol,1.0 equiv) in dichloromethane (5 mL) was added triethylamine (1.07 mL,7.71 mmol, 3.0 equiv) at 0° C. followed by addition of acetic anhydride(0.51 mL, 5.14 mmol, 2.0 equiv) dropwise. The reaction mixture wasstirred at room temperature for 2 h. It was poured over ice-water,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 1.4% methanol indichloromethane) to afford 69.5. MS (ES): m/z 237.3 [M+H]⁺.

Synthesis of compound 69.6. To a solution of 69.5 (0.4 g, 1.69 mmol, 1.0equiv) in DMF (5 mL) was added N-bromosuccinimide (0.448 g, 2.53 mmol,1.5 equiv) and stirred at room temperature for 1 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 80% ethylacetate in hexane as eluant) to afford 69.6. MS (ES): m/z 316.2 [M+H]⁺.

Synthesis of compound 69.7. Compound 69.7 was prepared from 69.6following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,1.4% methanol in dichloromethane as eluant). MS (ES): m/z 277.3 [M+H]⁺.

Synthesis of compound 69.8. To a solution of compound 69.7 (0.185 g,0.669 mmol, 1.0 equiv) in methanol (5 mL) was added potassium carbonate(1.846 g, 13.38 mmol, 20.0 equiv). The reaction mixture was heated toreflux for 16 h. It was poured over water, extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.0% methanol in dichloromethane as eluant) to afford69.8. MS (ES): m/z 235.3 [M+H]⁺.

Synthesis of compound 69.9. Compound 69.9 was prepared from 69.8following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 277.4 [M+H]⁺.

Synthesis of compound I-69. Compound I-69 was prepared from 69.9following the procedure described in the synthesis of I-1. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.5% methanol in dichloromethane as eluant). MS (ES): m/z: 515.46[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.57 (s, 1H), 8.25 (s, 1H),8.24-8.23 (d, J=2.0 Hz, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65 (s, 1H),7.52-7.50 (d, J=8.4 Hz, 1H), 7.34-7.33 (d, J=2.0 Hz, 1H), 7.20-7.19 (d,J=2.0 Hz, 1H), 6.89-6.87 (m, 1H), 6.63-6.61 (m, 1H), 5.01 (bs, 1H),4.03-4.00 (m, 2H), 3.69 (s, 3H), 3.52-3.47 (m, 2H), 2.02 (s, 3H),1.91-1.85 (m, 1H), 1.73-1.70 (m, 2H), 1.11-1.07 (m, 2H), 0.89-0.84 (m,2H), 0.65-0.63 (m, 2H).

Example 70:N-(4-((2-((5-cyclopropyl-1-((1-(hydroxymethyl)cyclopropyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 70.2. To a solution of 70.1 (2.0 g, 19.58 mmol,1.0 equiv) in DMF (20 mL) was added sodium hydride (0.798 g, 16.64 mmol,0.85 equiv) at 0° C. and stirred for 30 min. Benzyl bromide (2.34 g,13.70 mmol, 0.7 equiv) was added. The reaction mixture was stirred at 0°C. for 2 h. It was poured over ice, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 12% ethyl acetate in hexane as eluant) toafford 70.2. MS (ES): m/z 193.3 [M+H]⁺.

Synthesis of compound 70.3. To a solution of 70.2 (1.05 g, 5.46 mmol,1.0 equiv) in dichloromethane (10 mL) was added triethylamine (2.28 mL,16.38 mmol, 3.0 equiv) at 0° C. followed by addition of methanesulfonylchloride (1.27 mL, 16.38 mmol, 3.0 equiv). The reaction mixture wasstirred at room temperature for 1 h. It was poured over ice-water,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 70.3. MS (ES): m/z271.3 [M+H]⁺.

Synthesis of compound 70.4. To a solution of 70.3 (0.4 g, 1.83 mmol, 1.0equiv) in DMF (20 mL) was added potassium carbonate (0.505 g, 3.66 mmol,2.0 equiv) and tetra-butyl ammonium iodide (0.073 g, 0.201 mmol, 0.11equiv) followed by 61.1 (0.987 g, 3.65 mmol, 2.0 equiv). The reactionmixture was stirred at 50° C. for 4 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 50% ethyl acetate inhexane as eluant) to afford 70.4. MS (ES): m/z 394.2 [M+H]⁺.

Synthesis of compound 70.5. Compound 70.5 was prepared from 70.4following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,70% ethyl acetate in hexane as eluant). MS (ES): m/z 355.4 [M+H]⁺.

Synthesis of compound 70.6. A mixture of 70.5 (0.200 g, 0.564 mmol, 1.0equiv) and iron powder (0.157 g, 2.82 mmol, 5.0 equiv) in methanol (5mL) and water (1 mL) was added a few drops of acetic acid. The reactionmixture was stirred at 90° C. for 2 h. It was filtered through a pad ofCelite® and rinsed with methanol. The filtrate was concentrated underreduced pressure to obtain 70.6. MS (ES): m/z 325.4 [M+H]⁺.

Synthesis of compound 70.7. Compound 70.7 was prepared from 70.6following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 367.4 [M+H]⁺.

Synthesis of compound I-70. To a solution of Int-2 (0.074 g, 0.272 mmol,1.0 equiv) in THF (2 mL) was added 70.7 (0.100 g, 0.272 mmol, 1.0 equiv)followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.103 g, 0.544 mmol, 2.0 equiv). The reaction mixture was stirred at70° C. for 2 h. It was cooled to room temperature, poured over ice-waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain product that was dissolvedin dichloromethane (2 mL) and triflic acid (0.5 mL) was added dropwiseat 0° C. The reaction mixture was stirred at 0° C. for 30 min, pouredover saturated sodium bicarbonate solution and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4% methanol in dichloromethane as eluant) toafford I-70. MS (ES): m/z: 515.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ10.50 (s, 1H), 8.33 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H),7.65 (s, 1H), 7.53-7.50 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 7.11 (s, 1H),6.90-6.88 (d, J=8.4 Hz, 1H), 6.63-6.61 (m, 1H), 4.03 (s, 2H), 3.70 (s,3H), 3.19 (s, 2H), 2.02 (s, 3H), 1.85-1.81 (m, 1H), 0.88-0.87 (m, 2H),0.69 (bs, 2H), 0.59-0.58 (m, 2H), 0.44 (bs, 2H).

Example 71:N-(4-((2-((5-cyclopropyl-1-(oxazol-2-ylmethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 71.2. To a solution of 71.1 (1.0 g, 10.09 mmol,1.0 equiv) in DMF (10 mL) was added triethylamine (1.82 mL, 13.11 mmol,1.3 equiv) at 0° C. followed by addition of methanesulfonyl chloride(1.00 mL, 13.11 mmol, 1.3 equiv). The reaction mixture was stirred atroom temperature for 1 h. It was poured over ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 71.2. MS (ES): m/z 178.2[M+H]⁺.

Synthesis of compound 71.3. To a solution of 61.1 (1.0 g, 5.64 mmol, 1.0equiv) in DMF (10 mL) was added cesium carbonate (3.66 g, 11.28 mmol,2.0 equiv) and stirred for 15 min. To the mixture was added 71.2 (1.24g, 7.00 mmol, 1.2 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluant) toafford 71.3. MS (ES): m/z 301.1 [M+H]⁺.

Synthesis of compound 71.4. Compound 71.4 was prepared from 71.3following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.5% methanol in dichloromethane as eluant). MS (ES): m/z 262.2 [M+H]⁺.

Synthesis of compound 71.5. A mixture of compound 71.4 (0.070 g, 0.267mmol, 1.0 equiv) and 10% palladium on carbon (0.040 g) in methanol (5mL) was stirred at rt under 1 atm hydrogen for 2 h. It was filteredthrough a pad of Celite® and rinsed with methanol. The filtrate wasconcentrated under reduced pressure to obtain 71.5. MS (ES): m/z 232.3[M+H]⁺.

Synthesis of compound 71.6. Compound 71.6 was prepared from 71.5following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 274.3 [M+H]⁺.

Synthesis of compound I-71. Compound I-71 was prepared from 71.6 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3% methanol in dichloromethane as eluant). MS (ES): m/z:512.4 [M+H]⁺, ¹H NMR (CDCl₃, 400 MHz): δ 8.46 (s, 1H), 8.20 (s, 1H),8.08-8.07 (d, J=5.6 Hz, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.69 (s, 1H),7.63-7.61 (d, J=8.8 Hz, 1H), 7.15 (s, 1H), 6.94 (bs, 2H), 6.88 (s, 1H),6.58 (bs, 1H), 5.34 (bs, 2H), 3.66 (s, 3H), 2.18 (s, 3H), 1.83-1.81 (m,1H), 0.93-0.91 (m, 2H), 0.70-0.69 (m, 2H).

Example 72:N-(4-((2-((5-cyclopropyl-1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 72.1. Compound 73.1 was prepared from 61.1following the procedure described in the synthesis of 52.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,7-8% ethyl acetate in hexane as eluant). MS (ES): m/z 278.1 [M+H]⁺.

Synthesis of compound 72.2. Compound 72.2 was prepared from 72.1following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,30% ethyl acetate in hexane as eluant). MS (ES): m/z 239.2 [M+H]⁺.

Synthesis of compound 72.3. Compound 72.3 was prepared from 72.2following the procedure described in the synthesis of 52.4. The crudeproduct was used in the next step without further purification. MS (ES):m/z 209.3 [M+H]⁺.

Synthesis of compound 72.4. Compound 72.4 was prepared from 72.3following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 251.3 [M+H]⁺.

Synthesis of I-72. To a solution of Int-5 (0.071 g, 0.259 mmol, 1.0equiv) in 1,4-dioxane (2 mL) was added 72.4 (0.065 g, 0.259 mmol, 1.0equiv) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.098 g, 0.518 mmol, 2.0 equiv). The reaction mixture wasstirred at 100° C. for 2 h. It was cooled to room temperature, pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 3.0%methanol in dichloromethane as eluant) to afford I-72. MS (ES): m/z:490.40 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.57 (s, 1H), 8.35 (s, 1H),8.33 (s, 1H), 8.22-8.21 (d, J=5.6 Hz, 1H), 7.98-7.96 (d, J=8.4 Hz, 1H),7.78 (s, 1H), 7.14 (s, 1H), 6.93-6.91 (d, J=8.4 Hz, 1H), 6.77-6.75 (m,1H), 4.16-4.15 (m, 2H), 3.65 (bs, 5H), 3.27 (s, 3H), 2.06 (s, 3H),1.82-1.81 (m, 1H), 0.88-0.86 (m, 2H), 0.60-0.59 (m, 2H).

Example 73:N-(4-((2-((5-cyclopropyl-1-((1s,3s)-3-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 73.3. To a mixture of 73.1 (5.0 g, 32.44 mmol, 1.0equiv) and 73.2 (5.21 g, 42.17 mmol, 1.3 equiv) in DMF (50 mL) was addeddiisopropylethylamine (11.1 mL, 64.88 mmol, 2.0 equiv) at 0° C. Thereaction mixture was stirred at 0° C. for 2 h and was addedN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.7 g,45.36 mmol, 1.4 equiv) and 4-dimethylaminopyridine (0.989 g, 8.11 mmol,0.25 equiv). It was allowed to warm to rt and stirred for 16 h. It waspoured over water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 2.5%methanol in dichloromethane) to afford 73.3. MS (ES): m/z 224.09 [M+H]⁺.

Synthesis of compound 73.4. To a solution of lithium hydroxide (1.22 g,29.1 mmol, 5.0 equiv) in THF:water (15 mL, 2:1) was added 73.3 (1.3 g,5.82 mmol, 1.0 equiv). The reaction was stirred at room temperature for24 h. Most organic solvents were removed under reduced pressure. Theaqueous residue was acidified with 1 N hydrochloric acid to approx. pH3. It was extracted with 10% methanol in dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to obtain73.4. MS (ES): m/z 210.2 [M+H]⁺.

Synthesis of compound 73.5. A solution of 73.4 (0.8 g, 3.82 mmol, 1.0equiv) and triethylamine (0.91 mL, 6.49 mmol, 1.7 equiv) in tert-butanol(15 mL) was added diphenyl phosphoryl azide (1.36 g, 4.96 mmol, 1.3equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 16h. It cooled to room temperature, poured over water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1.5% methanol in dichloromethane to obtain73.5. MS (ES): m/z 281.3 [M+H]⁺.

Synthesis of compound 73.6. To a solution of 73.5 (0.4 g, 1.43 mmol, 1.0equiv) in acetonitrile (10 mL) at 0° C. was N-bromosuccinimide (0.354 g,2.00 mmol, 1.4 equiv) in portions. The reaction mixture was stirred at0° C. for 15 min. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane as eluant) toafford 73.6. MS (ES): m/z 360.2 [M+H]⁺.

Synthesis of compound 73.7. Compound 73.7 was prepared from 73.6following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,70% ethyl acetate in hexane as eluant). MS (ES): m/z 321.4 [M+H]⁺.

Synthesis of compound 73.8. To a solution of 73.7 (0.059 g, 0.184 mmol,1 equiv) in dioxane (2 mL) at 0° C. was added 4 N hydrochloric acid indioxane (1 mL) dropwise. The reaction mixture was stirred at roomtemperature for 30 min. It was poured over saturated aqueous solution ofsodium bicarbonate and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to obtain73.8. MS (ES): m/z 221.3 [M+H]⁺.

Synthesis of compound 73.9. Compound 73.9 was prepared from 73.8following the procedure described in the synthesis of 1.2. The crudeproduct was used in the next step without further purification. MS (ES):m/z 263.3 [M+H]⁺.

Synthesis of compound I-73. Compound I-73 was prepared from 73.9 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 4% methanol in dichloromethane as eluant). MS (ES): m/z:501.7 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 8.25 (bs, 2H),8.16-8.14 (d, J=5.6 Hz, 1H), 7.64 (s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H),7.34 (s, 1H), 7.20 (s, 1H), 6.90-6.88 (m, 1H), 6.63-6.61 (m, 1H), 5.27(bs, 1H), 4.68-4.64 (m, 1H), 4.06-3.98 (m, 1H), 3.69 (s, 3H), 2.18-2.11(m, 2H), 2.02 (s, 3H), 1.94-1.87 (m, 1H), 1.23-1.16 (m, 2H), 0.91-0.86(m, 2H), 0.65-0.61 (m, 2H).

Example 74:N-(4-((2-((1-((1r,3r)-3-cyanocyclobutyl)-5-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 74.2. To a solution of 74.1 (1.0 g, 10.52 mmol,1.0 equiv) in methanol (10 mL) was added sodium borohydride (0.778 g,21.04 mmol, 2.0 equiv) in small portions at 0° C. The reaction mixturewas stirred at room temperature for 3 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 74.2. ¹H NMR (CDCl₃,400 MHz): 4.35-4.27 (m, 1H), 2.83-2.79 (m, 2H), 2.69-2.58 (m, 1H),2.41-2.34 (m, 2H), 2.00 (bs, 1H).

Synthesis of compound 74.3. To a solution of 74.2 (0.600 g, 6.18 mmol,1.0 equiv) in dichloromethane (10 mL) was added triethylamine (2.58 mL,18.54 mmol, 3.0 equiv) at 0° C. followed by addition of methanesulfonylchloride (0.571 mL, 7.41 mmol, 1.2 equiv). The reaction mixture wasstirred at room temperature for 2 h. It was poured over ice-water,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 15% ethylacetate in hexane as eluant) to afford 74.3. ¹H NMR (CDCl₃, 400 MHz):5.03-4.96 (m, 1H), 3.18-3.12 (m, 1H), 3.07 (s, 3H), 2.98-2.94 (m, 2H),2.87-2.61 (m, 2H).

Synthesis of compound 74.4. To a solution of3-amino-5-bromopyridin-2(1H)-one (0.5 g, 2.65 mmol, 1.0 equiv) intoluene (5 mL) was added acetic anhydride (0.30 mL, 3.18 mmol, 1.2equiv). The reaction mixture was heated to reflux for 2 h. It wasconcentrated under reduced pressure, and the residue was purified bytrituration with diethyl ether to obtain 74.4. MS (ES): m/z 232.2[M+H]⁺.

Synthesis of compound 74.5. To a solution of 74.3 (0.900 g, 5.14 mmol,1.0 equiv) and 74.4 (1.19 g, 5.14 mmol, 1.0 equiv) in DMF (10 mL) wasadded potassium carbonate (1.773 g, 12.85 mmol, 2.5 equiv). The reactionmixture was stirred at 90° C. for 16 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 25% ethylacetate in hexane as eluant) to afford 74.5. MS (ES): m/z 311.2 [M+H]⁺.

Synthesis of compound 74.6. Compound 74.6 was prepared from 74.5following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,25% ethyl acetate in hexane as eluant). MS (ES): m/z 272.3 [M+H]⁺.

Synthesis of compound 74.7 and 74.8. To a solution of 74.6 (0.150 g,0.552 mmol, 1.0 equiv) in methanol (5 mL) was added potassium carbonate(1.52 g, 11.04 mmol, 20 equiv). The reaction mixture was stirred at 100°C. for 16 h. It was poured over ice-water, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 15% ethyl acetate in hexane as eluant) toafford mixture of 74.7 and 74.8. This was further separated on SFCpurification to obtain 74.7, MS (ES): m/z 230.3 [M+H]⁺ and 74.8, MS(ES): m/z 230.3 [M+H]⁺.

Synthesis of compound 74.9. Compound 74.9 was prepared from 74.7following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 272.3 [M+H]⁺.

Synthesis of I-74. Compound I-74 was prepared from 74.9 and Int-2following the procedure described in the synthesis of I-1. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.2% methanol in dichloromethane as eluant). MS (ES): m/z: 510.48[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1H), 8.27 (s, 1H), 8.16(s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.47-7.45 (d, J=6.8Hz, 1H), 7.30 (s, 1H), 6.89-6.87 (d, J=7.6 Hz, 1H), 6.63 (s, 1H), 5.42(s, 1H), 3.70 (s, 3H), 3.46 (bs, 1H), 2.77 (bs, 2H), 2.67 (bs, 2H), 2.02(s, 3H), 1.93 (bs, 1H), 0.95-0.94 (m, 2H), 0.66 (bs, 2H).

Example 75:N-(4-((2-((5-cyclopropyl-1-(((1S,2R)-2-hydroxycyclopentyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-cyclopropyl-1-((1R,2S)-2-hydroxycyclopentyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound trans-(±)-75.2. To a solution of 75.1 (10 g, 64.03mmol, 1.0 equiv) in diethyl ether (100 mL) was added lithium aluminumhydride solution (1 M in THF, 89 mL, 89.6 mmol, 1.4 equiv) at 0° C. Thereaction mixture was stirred at room temperature for 4 h. It was treatedwith ice-water (3 mL) and 15% sodium hydroxide (3 mL), filtered througha pad of Celite® and washed with diethyl ether. Organic layer dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2-2.4% methanol in dichloromethane as eluant)to afford trans-(±)-75.2. MS (ES): m/z 117.2 [M+H]⁺.

Synthesis of compound trans-(±)-75.3. To a solution of trans-(±)-75.2(1.5 g, 12.91 mmol, 1.0 equiv) in THF (15 mL) was addedtert-butyldimethylsilyl chloride (2.32 g, 15.49 mmol, 1.2 equiv)followed by imidazole (2.10 g, 30.98 mmol, 2.4 equiv). The mixture wasstirred at room temperature for 5 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 8-10% ethylacetate in hexane as eluant) to afford trans-(±)-75.3. MS (ES): m/z231.4 [M+H]⁺.

Synthesis of compound trans-(±)-75.4. To a solution of trans-(±)-75.3(1.2 g, 5.21 mmol, 1.0 equiv) in THF (12 mL) was added sodium hydride(0.5 g, 10.42 mmol, 2 equiv) at 0° C. and stirred for 1 h followed byaddition of benzyl bromide (1.336 g, 7.815 mmol, 1.5 equiv) andtetrabutylammonium iodide (0.192 g, 0.521 mmol, 0.1 equiv). The reactionmixture was stirred at room temperature for 12 h. It was poured overice, stirred and extracted with diethyl ether. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 5%ethyl acetate in hexane as eluant) to afford trans-(±)-75.4. MS (ES):m/z 321.5 [M+H]⁺.

Synthesis of compound trans-(±)-75.5. To a solution of trans-(±)-75.4(0.960 g, 2.99 mmol, 1.0 equiv) in THF (10 mL) was addedtetrabutylammoniumfluoride solution (1 M in THF, 3.6 mL, 3.58 mmol, 1.2equiv) at 0° C. and stirred for 1 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 15% ethylacetate in hexane as eluant) to afford trans-(±)-75.5. MS (ES): m/z207.3 [M+H]⁺.

Synthesis of compound trans-(±)-75.6. To a solution of trans-(±)-75.5(0.600 g, 14.32 mmol, 1.0 equiv) in dichloromethane (10 mL) was addedtriethylamine (2.9 mL, 21.48 mmol, 1.5 equiv) followed by addition ofmethanesulfonyl chloride (1.1 mL, 14.32 mmol, 1.0 equiv) at 0° C. andstirred at room temperature for 1 h. It was poured over ice, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain trans-(±)-75.6. MS (ES):m/z 285.4 [M+H]⁺.

Synthesis of compound trans-(±)-75.7. To a solution of 74.4 (0.610 g,2.15 mmol, 1.0 equiv) in DMF (10 mL) was added potassium carbonate(0.593 g, 4.3 mmol, 2.0 equiv) followed by trans-(±)-75.6 (0.495 g, 2.15mmol, 1.0 equiv). The reaction mixture stirred at 65° C. for 2 h. It waspoured over ice-water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,45% ethyl acetate in hexane as eluant) to afford (±)-75.7. MS (ES): m/z420.3 [M+H]⁺.

Synthesis of compound trans-(±)-75.8. Compound trans-(±)-75.8 wasprepared from (±)-75.7 following the procedure described in thesynthesis of 61.3. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 50% ethyl acetate in hexaneas eluant). MS (ES): m/z 381.5 [M+H]⁺.

Synthesis of compound trans-(±)-75.9. To a solution of trans-(±)-75.8(0.225 g, 0.591 mmol, 1.0 equiv) in methanol (5 mL) was added potassiumcarbonate (0.163 g, 1.182 mmol, 2.0 equiv). The mixture was heated toreflux for 16 h. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1.6% methanol in dichloromethane as eluant) toafford (±)-75.9. MS (ES): m/z 339.5 [M+H]⁺.

Synthesis of compound (±)-75.10. Compound (±)-75.10 was prepared from(±)-75.9 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 381.5 [M+H]⁺.

Synthesis of compound (±)-75.11. Compound (±)-75.11 was prepared from(±)-75.10 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 1.5% methanol in dichloromethane as eluant). MS (ES): m/z:619.7 [M+H]⁺.

Synthesis of compound (±)-I-75. To a solution of (±)-75.11 (0.125 g,0.202 mmol, 1.0 equiv) in dichloromethane (3 mL) was added triflic acid(0.5 mL) at 0° C. and stirred for 30 min. It was poured over ice-coldsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5-3.0% methanol indichloromethane as eluant) to afford (±)-I-75. MS (ES): m/z: 529.2[M+H]⁺.

I-75-a and I-75-b. Compound (±)-I-75 was separated on SFC (column:CHIRALPAK IH (250 mm×4.6 mm, 5 μm); mobile phase: 0.1% DEA in MEOH; flowrate: 4 mL/min) to afford first eluting fraction (I-75-a) and secondeluting fraction (I-75-b). (*Absolute stereochemistry not determined.)

I-75-a. MS (ES): m/z: 529.14 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.52(s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.16-8.15 (d, J=5.2 Hz, 1H), 7.66(s, 1H), 7.53-7.51 (d, J=8.4 Hz, 1H), 7.35-7.34 (d, J=2.0 Hz, 1H), 7.13(s, 1H), 6.90-6.88 (m, 1H), 6.64-6.62 (m, 1H), 4.62-4.61 (d, 1H),4.08-4.03 (m, 1H), 3.83-3.78 (t, 2H), 3.70 (s, 3H), 2.24 (bs, 2H), 2.03(s, 3H), 1.86-1.82 (m, 2H), 1.68-1.56 (m, 2H), 1.50-1.47 (m, 1H),1.34-1.24 (m, 1H), 0.88-0.86 (d, 2H), 0.61-0.60 (d, 2H).

I-75-b. MS (ES): m/z: 529.19 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.16-8.15 (d, J=5.2 Hz, 1H), 7.66(s, 1H), 7.53-7.51 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 7.13 (s, 1H),6.90-6.88 (d, J=6.8 Hz, 1H), 6.63-6.62 (m, 1H), 4.62-4.61 (d, 1H),4.05-4.03 (m, 1H), 3.83-3.78 (t, 2H), 3.70 (s, 3H), 2.24 (bs, 2H), 2.03(s, 3H), 1.86-1.83 (m, 2H), 1.64-1.60 (m, 2H), 1.50-1.47 (m, 1H),1.34-1.24 (m, 1H), 0.88-0.86 (d, 2H), 0.61-0.60 (d, 2H).

Example 76:N-(4-((2-((5-cyclopropyl-1-(((1R,2R)-2-methoxycyclobutyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-cyclopropyl-1-((1S,2S)-2-methoxycyclobutyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 76.2. To a solution of 76.1 (4.0 g, 33.27 mmol,1.0 equiv) in dichloromethane (75 mL) was added ethyl acrylate (7.33 g,78.99 mmol, 2.2 equiv) at 0° C. followed by addition of diethylaluminumchloride solution (1 M in hexane, 50 mL, 49.9 mmol, 1.5 equiv). Thereaction mixture was stirred at room temperature for 2-3 h. Aftercompletion of reaction, triethyl amine (5 mL) followed by 10% aqueoussodium bicarbonate was added, filtered through a pad of Celite® andwashed with dichloromethane. Organic layer dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,0.5% ethyl acetate in hexane as eluant) to afford 76.2. ¹H NMR (CDCl₃,400 MHz): δ 4.25-4.19 (m, 2H), 3.45-3.41 (m, 1H), 2.59-2.53 (m, 1H),2.34-2.30 (m, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 1.35-1.29 (t, 3H).

Synthesis of compound 76.3. To a solution of 76.2 (2.0 g, 9.08 mmol, 1.0equiv) in THF (20 mL) was added lithium aluminum hydride solution (1 Min THF, 13.6 mL, 13.62 mmol, 1.5 equiv) at 0° C. The reaction mixturewas stirred at room temperature for 1 h. After completion of reaction,saturated aqueous sodium sulfate was added, reaction mixture filteredthrough a pad of Celite® and washed with diethyl ether. Organic layerdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 8% ethyl acetate in hexane aseluant) to afford 76.3. ¹H NMR (CDCl₃, 400 MHz): δ 3.90-3.85 (m, 1H),3.79-3.75 (m, 1H), 2.75-2.68 (m, 1H), 2.34-2.22 (m, 3H), 2.11 (s, 3H),2.08 (s, 3H), 2.00-1.91 (m, 2H).

Synthesis of compound 76.4. To a solution of 76.3 (1.5 g, 8.41 mmol, 1.0equiv) in THF (15 mL) was added sodium hydride (0.807 g, 16.82 mmol, 2equiv) at 0° C. It was stirred for 1 h and was added benzyl bromide(1.72 g, 10.09 mmol, 1.2 equiv) and tetrabutylammonium iodide (0.031 g,0.0841 mmol, 0.01 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was poured over ice, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2% ethyl acetate in hexane as eluant) to afford76.4. ¹H NMR (CDCl₃, 400 MHz): δ 7.41-7.37 (m, 5H), 4.60-4.50 (m, 2H),3.80-3.75 (m, 1H), 3.52-3.48 (m, 1H), 2.92-2.89 (m, 1H), 2.30-2.19 (m,3H), 2.09 (s, 3H), 2.05 (s, 2H), 1.29 (bs, 2H).

Synthesis of compound 76.5. To a solution of silver nitrate (3.87 g,22.81 mmol, 3.4 equiv) and N-chlorosuccinimide (2.67 g, 20.13 mmol, 3.0equiv) in acetonitrile (10 mL) and water (1.8 mL) at 0° C. was added76.4 (1.8 g, 6.71 mmol, 1.0 equiv) in acetonitrile (6 mL) and stirredfor 30 min. It was poured over saturated aqueous sodium sulfitesolution, stirred and precipitated solid was filtered washed with ethylacetate. Organic layer separated washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5% ethyl acetate in hexane as eluant) to afford 76.5. ¹HNMR (CDCl₃, 400 MHz): δ 7.39-7.32 (m, 5H), 4.59-4.53 (m, 2H), 3.77-3.73(m, 1H), 3.65-3.57 (m, 2H), 3.11-3.04 (m, 2H), 2.26-2.04 (m, 2H).

Synthesis of compound (±)-76.6. To a solution of 76.5 (1.0 g, 5.26 mmol,1.0 equiv) in THF (10 mL) was added L-selectride (1.49 g, 7.89 mmol, 1.5equiv) at −78° C. and stirred for 30 min. It was poured over ice-waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 10% ethyl acetate inhexane as eluant) to afford (±)-76.6. ¹H NMR (CDCl₃, 400 MHz): δ7.37-7.26 (m, 5H), 4.84-4.82 (m, 1H), 4.50-4.44 (m, 1H), 4.24-4.20 (m,1H), 3.67-3.56 (m, 1H), 2.15-2.10 (m, 1H), 1.95-1.87 (m, 1H), 1.67-1.50(m, 2H), 1.36-1.33 (m, 1H), 0.86-0.81 (m, 2H).

Synthesis of compound (±)-76.7. To a solution of (±)-76.6 (0.700 g, 3.64mmol, 1.0 equiv) in DMF (10 mL) was added sodium hydride (0.436 g, 10.92mmol, 3.0 equiv) in small portions at 0° C. and stirred for 20 min. Tothe mixture was added methyl iodide (1.033 g, 7.28 mmol, 2.0 equiv). Thereaction mixture was stirred at room temperature for 16 h. It was pouredover ice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,8% ethyl acetate in hexane as eluant) to afford (±)-76.7. MS (ES): m/z207.3 [M+H]⁺.

Synthesis of compound (±)-76.8. A mixture of compound (±)-76.7 (0.600 g,2.91 mmol, 1.0 equiv), methanol (10 mL) and 10% palladium on carbon(0.300 g) was stirred at rt under 1 atm hydrogen for 2 h. It wasfiltered through a pad of Celite® and rinsed with methanol. The filtratewas concentrated under reduced pressure to obtain (±)-76.8. ¹H NMR(DMSO-d6, 400 MHz): δ 4.26-4.23 (m, 1H), 3.89-3.84 (m, 1H), 3.67-3.62(m, 1H), 3.50-3.44 (m, 1H), 3.12 (s, 3H), 2.11-2.09 (m, 1H), 1.94-1.85(m, 1H), 1.63-1.46 (m, 2H).

Synthesis of compound (±)-76.9. To a solution of (±)-76.8 (0.300 g, 2.58mmol, 1.0 equiv) and triethylamine (1.07 mL, 7.74 mmol, 3.0 equiv) indichloromethane (5 mL) was added methanesulfonyl chloride (0.4 mL, 5.16mmol, 2.0 equiv) at 0° C. and stirred at room temperature for 2 h. Itwas poured over ice, stirred and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain (±)-76.9. MS (ES): m/z 195.3 [M+H]⁺.

Synthesis of compound (±)-76.10. To a solution of 74.4 (0.350 g, 1.51mmol, 1.0 equiv) in DMF (5 mL) was added potassium carbonate (0.416 g,3.02 mmol, 2.0 equiv) followed by (±)-76.9 (0.35 g, 1.82 mmol, 1.2equiv). The reaction mixture stirred at 90° C. for 24 h. It was pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 11%ethyl acetate in hexane as eluant) to afford (±)-76.10. MS (ES): m/z330.2 [M+H]⁺.

Synthesis of compound (±)-76.11. Compound (±)-76.11 was prepared from(±)-76.10 following the procedure described in the synthesis of 61.3.The product was purified by flash column chromatography on silica gel(CombiFlash®, 1% methanol in dichloromethane as eluant). MS (ES): m/z291.4 [M+H]⁺.

Synthesis of compound (±)-76.12. A mixture of (±)-76.11 (0.163 g, 0.561mmol, 1.0 equiv) and potassium carbonate (1.54 g, 11.22 mmol, 20.0equiv) in methanol (5 mL) was added heated to reflux for 16 h. It waspoured over ice-water and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.6% methanol in dichloromethane as eluant) to afford (±)-76.12. MS(ES): m/z 249.3 [M+H]⁺.

Synthesis of compound (±)-76.13. Compound (±)-76.13 was prepared from(±)-76.12 following the procedure described in the synthesis of 11.8.The crude product was used in the next step without furtherpurification. MS (ES): m/z 291.4 [M+H]⁺.

Synthesis of compound (±)-I-76. Compound (±)-I-76 was prepared from(±)-76.13 and Int-2 following the procedure described in the synthesisof I-1 The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES):m/z: 529.6 [M+H]⁺.

I-76-a and I-76-b. (±)-I-76 was separated on HPLC (column: CHIRALPAKIB-N (250 mm×4.6 mm, 5 μm); mobile phase: (A) 0.1% diethylamine inn-hexane (B) 0.1% diethylamine in 2-propanol:acetonitrile (70:30); flowrate: 20 mL/min) to afford first eluting fraction (I-76-a) and secondeluting fraction (I-76-b). (*Absolute stereochemistry not determined.)

I-76-a. MS (ES): m/z: 530.09 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.18 (s, 1H),6.89-6.87 (d, J=8.0 Hz, 1H), 6.62 (bs, 1H), 4.29-4.23 (m, 1H), 4.08-4.06(m, 1H), 3.95-3.93 (m, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.97 (bs, 1H),2.15-2.13 (m, 1H), 2.02 (s, 3H), 1.56 (bs, 2H), 1.23 (bs, 2H), 0.86 (bs,2H), 0.59 (bs, 2H).

I-76-b. MS (ES): m/z: 529.6 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.18 (s, 1H),6.89-6.87 (d, J=8.0 Hz, 1H), 6.62-6.61 (m, 1H), 4.29-4.23 (m, 1H),4.10-4.05 (m, 1H), 3.97-3.92 (m, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.96(bs, 1H), 2.17-2.11 (m, 1H), 2.02 (s, 3H), 1.58-1.56 (m, 2H), 1.17 (bs,2H), 0.87 (bs, 2H), 0.59 (bs, 2H).

Example 77:N-(4-((2-((5-cyclopropyl-1-(((1R,2R)-2-hydroxycyclobutyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-cyclopropyl-1-(((1S,2S)-2-hydroxycyclobutyl)methyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 77.1. To a solution of 76.3 (2.4 g, 13.46 mmol,1.0 equiv) in dichloromethane (25 mL) was added triethylamine (5.62 mL,40.38 mmol, 3.0 equiv) followed by addition of methanesulfonyl chloride(2.1 mL, 26.92 mmol, 2.0 equiv) at 0° C. and stirred at room temperaturefor 3 h. It was poured over ice, stirred and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 77.1. MS (ES): m/z 257.4 [M+H]⁺.

Synthesis of compound 77.2. To a solution of 74.4 (1.6 g, 6.92 mmol, 1.0equiv) in DMF (20 mL) was added potassium carbonate (1.90 g, 13.84 mmol,2.0 equiv) followed by 77.1 (2.31 g, 9.0 mmol, 1.3 equiv). The reactionmixture stirred at 90° C. for 24 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 30% ethyl acetate inhexane as eluant) to afford 77.3. MS (ES): m/z 392.3 [M+H]⁺.

Synthesis of compound 77.3. To a solution of silver nitrate (1.167 g,6.868 mmol, 3.4 equiv) and N-chlorosuccinimide (2.67 g, 20.13 mmol, 3.0equiv) in acetonitrile (12 mL) and water (2 mL) at 0° C. was added 77.2(0.790 g, 2.02 mmol, 1.0 equiv) in acetonitrile (8 mL) and stirred for30 min. It was poured over saturated aqueous sodium sulfite solution,stirred and precipitated solid was filtered washed with ethyl acetate.Organic layer separated washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,ethyl acetate as eluant) to afford 77.3. MS (ES): m/z 314.3 [M+H]⁺.

Synthesis of compound (±)-77.4 To a solution of 77.3 (0.500 g, 1.60mmol, 1.0 equiv) in THF (10 mL) was added L-selectride (0.456 g, 2.4mmol, 1.5 equiv) at −78° C. and stirred for 30 min. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 1.2% methanol indichloromethane as eluant) to afford (±)-77.4. MS (ES): m/z 316.2[M+H]⁺.

Synthesis of compound (±)-77.5. Compound (±)-77.5 was prepared from(±)-77.4 following the procedure described in the synthesis of 61.3. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 1.8% methanol in dichloromethane as eluant). MS (ES): m/z277.3 [M+H]⁺.

Synthesis of compound (±)-77.6. A mixture of (±)-77.5 (0.160 g, 0.579mmol, 1.0 equiv), methanol (5 mL) and potassium carbonate (1.59 g, 11.58mmol, 20.0 equiv) was heated to reflux for 16 h. It was poured overice-water and extracted with dichloromethane. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 2.0%methanol in dichloromethane as eluant) to afford (±)-77.6. MS (ES): m/z235.3 [M+H]⁺.

Synthesis of compound (±)-77.7. Compound (±)-77.7 was prepared from(±)-77.6 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 277.4 [M+H]⁺.

Synthesis of compound (±)-I-77. Compound (±)-I-77 was prepared from(±)-77.7 and Int-2 following the procedure described in the synthesis ofI-1. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.5% methanol in dichloromethane as eluant). MS (ES):m/z: 515.5 [M+H]⁺.

I-77-a and I-77-b. Compound (±)-I-77 was separated on SFC (columnCHIRALPAK 1H (250 mm×4.6 mm, 5 μm); mobile phase: 0.1% diethylamine inMeOH; flow rate: 4 mL/min) to afford first eluting fraction (I-77-a) andsecond eluting fraction (I-77-b). (*Absolute stereochemistry notdetermined.)

I-77-a. MS (ES): m/z: 515.6 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H),6.89-6.87 (d, J=8.4 Hz, 1H), 6.63-6.61 (d, J=4.4 Hz, 1H), 4.34-4.19 (m,2H), 4.15-4.10 (m, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.82 (bs, 1H), 2.16(bs, 1H), 2.03 (s, 2H), 1.81 (bs, 1H), 1.60-1.58 (d, 1H), 1.24 (bs, 1H),0.87-0.85 (d, 2H), 0.60-0.59 (d, 2H).

I-77-b. MS (ES): m/z: 515.7 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H),6.90-6.87 (d, J=8.4 Hz, 1H), 6.63-6.62 (d, J=3.6 Hz, 1H), 4.34-4.19 (m,2H), 4.15-4.10 (m, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.81 (bs, 1H), 2.17(bs, 1H), 2.03 (s, 2H), 1.81 (bs, 1H), 1.60-1.58 (d, 1H), 1.24 (bs, 1H),0.87-0.85 (d, 2H), 0.60-0.59 (d, 2H).

Example 78:N-(4-((2-((5-cyclopropyl-1-((1R,2S)-2-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-cyclopropyl-1-((1S,2R)-2-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound cis-(±)-78.3. To a solution of 78.1 (2.0 g, 12.98mmol, 1.0 equiv) and (±)-78.2 (1.92 g, 15.57 mmol, 1.2 equiv) in DMF (20mL) was added diisopropylethylamine (4.5 mL, 25.96 mmol, 2.0 equiv) at0° C. The reaction mixture was stirred for 2 h and was addedN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.48 g,18.17 mmol, 1.4 equiv) and 4-dimethylaminopyridine (0.395 g, 3.24 mmol,0.25 equiv). The reaction mixture was stirred at room temperature for 16h. It was poured over water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography and the compound waseluted in 2.0% methanol in dichloromethane to obtain (±)-78.3. MS (ES):m/z 224.09 [M+H]⁺.

Synthesis of compound cis-(±)-78.4. To a solution of lithium hydroxide(1.50 g, 35.85 mmol, 5.0 equiv) in THF:methanol:water (15 mL, 2:1:1) wasadded cis-(±)-78.3 (1.6 g, 7.17 mmol, 1.0 equiv) and stirred at roomtemperature for 24 h. Most organic solvent was removed under reducedpressure. The aqueous residue was acidified with 1 N hydrochloric acidto adjust approx. pH 3. It was extracted with 10% methanol indichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain cis-(±)-78.4. MS (ES): m/z 210.2 [M+H]⁺.

Synthesis of compound cis-(±)-78.5. To a solution of cis-(±)-78.4 (1.1g, 5.26 mmol, 1.0 equiv) in tert-butanol (10 mL) was added triethylamine(2.19 mL, 15.78 mmol, 3.0 equiv) and diphenylphosphorylazide (3.6 g,13.15 mmol, 2.5 equiv) under nitrogen. The mixture was stirred at 80° C.for 16 h. It cooled to room temperature, poured over water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 1.2% methanol indichloromethane to obtain cis-(±)-78.5. MS (ES): m/z 281.3 [M+H]⁺.

Synthesis of compound cis-(±)-78.6. To a solution of cis-(±)-78.5 (0.6g, 2.14 mmol, 1.0 equiv) in dichloromethane (10 mL) at 0° C. was addedpyridinium tribromide (1.03 g, 3.21 mmol, 1.5 equiv) portionwise. Thereaction mixture stirred at room temperature for 4 h. It concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexaneas eluant) to afford cis-(±)-78.6. MS (ES): m/z 360.2 [M+H]⁺.

Synthesis of compound cis-(±)-78.7. Compound cis-(±)-78.7 was preparedfrom cis-(±)-78.6 following the procedure described in the synthesis of61.3. The product was purified by flash column chromatography on silicagel (CombiFlash®, 30% ethyl acetate in hexane as eluant). MS (ES): m/z321.4 [M+H]⁺.

Synthesis of compound cis-(±)-78.8. To a solution of cis-(±)-78.7 (0.110g, 0.343 mmol, 1.0 equiv) in dioxane (1 mL) was added 4 N hydrochloricacid in dioxane (1 mL) dropwise at 0° C. The reaction mixture wasstirred at room temperature for 30 min. It was poured over saturatedaqueous solution of sodium bicarbonate and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain cis-(±)-78.8. MS (ES): m/z 221.3 [M+H]⁺.

Synthesis of compound cis-(±)-78.9. Compound cis-(±)-78.9 was preparedfrom cis-(±)-78.8 following the procedure described in the synthesis of11.8. The crude product was used in the next step without furtherpurification. MS (ES): m/z 263.3 [M+H]⁺.

Synthesis of compound cis-(±)-I-78. Compound cis-(±)-I-78 was preparedfrom cis-(±)-78.9 and Int-2 following the procedure described in thesynthesis of I-1. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 4% methanol indichloromethane as eluant). MS (ES): m/z: 501.7 [M+H]⁺.

I-78-a and I-78-b. Compound (±)-I-78 was separated on HPLC (column:CHIRALPAK IB-N (250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% diethylaminein n-hexane (B) 0.1% diethylamine in 2-propanol:acetonitrile (70:30);flow rate: 20 mL/min) to afford first eluting fraction (I-78-a) andsecond eluting fraction (I-78-b). (*Absolute stereochemistry notdetermined.)

I-78-a. MS (ES): m/z: 501.1 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (bs, 1H), 7.17 (s, 1H),6.89-6.87 (m, 1H), 6.63-6.61 (m, 1H), 5.20-5.15 (m, 1H), 4.51 (bs, 1H),3.69 (s, 3H), 2.79-2.72 (m, 1H), 2.02 (s, 3H), 1.91-1.86 (m, 1H),1.75-1.70 (m, 1H), 1.23 (bs, 1H), 1.11-1.03 (m, 2H), 0.89-0.87 (m, 2H),0.62-0.59 (m, 2H).

I-78-b. MS (ES): m/z: 501.2 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.17 (s, 1H),6.89-6.87 (m, 1H), 6.63-6.61 (m, 1H), 5.19-5.15 (m, 1H), 4.51 (bs, 1H),3.69 (s, 3H), 2.79-2.72 (m, 1H), 2.02 (s, 3H), 1.90 (bs, 1H), 1.76-1.70(m, 1H), 1.23 (bs, 1H), 1.11-1.03 (m, 2H), 0.89-0.87 (m, 2H), 0.62 (bs,2H).

Example 79:N-(4-((2-((5-cyclopropyl-1-((1R,2R)-2-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-cyclopropyl-1-((1S,2S)-2-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-I-79. Compound (±)-I-79 was prepared fromcompound 78.1 and (±)-79.1 following the procedures described in eachstep in the synthesis of (±)-I-78. The product was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.5% methanol indichloromethane as eluant). MS (ES): m/z: 501.7 [M+H]⁺.

I-79-a and I-79-b. Compound (±)-I-79 was separated on HPLC (column:CHIRALPAK IH (250 mm×21 mm, 5 μm); mobile phase (A) 0.1% diethylamine inn-hexane (B) 0.1% diethylamine in 2-propanol:acetonitrile (70:30); flowrate: 20 mL/min) to afford first eluting fraction (I-79-a) and secondeluting fraction (I-79-b). (*Absolute stereochemistry not determined.)

I-79-a. MS (ES): m/z: 501.2 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.15-8.14 (d, J=5.2 Hz, 1H), 7.64(s, 1H), 7.52-7.50 (d, J=8.4 Hz, 1H), 7.33 (bs, 1H), 7.20 (s, 1H),6.89-6.87 (d, J=8.4 Hz, 1H), 6.62-6.61 (d, J=3.6 Hz, 1H), 5.62-5.60 (d,J=6.4 Hz, 1H), 4.92-4.87 (m, 1H), 4.44-4.40 (m, 1H), 3.69 (s, 3H),2.13-2.08 (m, 2H), 2.02 (s, 3H), 1.87 (bs, 1H), 1.23 (bs, 1H), 1.14-1.07(m, 1H), 0.88-0.86 (m, 2H), 0.64 (bs, 2H).

I-79-b. MS (ES): m/z: 501.2 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.50(s, 1H), 8.28 (s, 1H), 8.28 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.65(s, 1H), 7.53-7.51 (d, J=8.4 Hz, 1H), 7.34 (bs, 1H), 7.21 (s, 1H),6.90-6.88 (d, J=8.0 Hz, 1H), 6.63 (bs, 1H), 5.63-5.61 (d, J=6.8 Hz, 1H),4.92-4.90 (m, 1H), 4.45-4.43 (m, 1H), 3.70 (s, 3H), 2.12-2.09 (m, 2H),2.03 (s, 3H), 1.88 (bs, 1H), 1.24 (bs, 1H), 1.14-1.10 (m, 1H), 0.89-0.87(m, 2H), 0.65 (bs, 2H).

Example 80:N-(4-((2-((1-isopropyl-2-oxo-5-(1H-pyrazol-1-yl)-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 80.1. A mixture of 65.2 (0.3 g, 1.15 mmol, 1.0equiv), 1,4-dioxane (12 mL), pyrazole (0.093 g, 1.38 mmol, 1.2 equiv)and potassium carbonate (0.396 g, 2.87 mmol, 2.5 equiv) was degassed bybubbling argon for 10 min and added 1,2-dimethylethylenediamine (0.015g, 0.172 mmol, 0.15 equiv) and copper iodide (0.065 g, 0.345 mmol, 0.3equiv). The reaction mixture was degassed for 5 min and was stirred at100° C. for 12 h. It was cooled to room temperature, poured over water,extracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 25% ethyl acetate inhexane as eluant) to afford 80.1. MS (ES): m/z 249.2 [M+H]⁺.

Synthesis of compound 80.2. A mixture of compound 80.1 (0.150 g, 0.604mmol, 1.0 equiv), methanol (5 mL) and 10% palladium on carbon (0.065 g)was stirred at rt under 1 atm hydrogen for 2 h. It was filtered througha pad of Celite® and rinsed with methanol. The filtrate was concentratedunder reduced pressure to obtain 80.2. MS (ES): m/z 219.3 [M+H]⁺.

Synthesis of compound 80.3. Compound 80.3 was prepared from 80.2following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 261.3 [M+H]⁺.

Synthesis of compound I-80. Compound I-80 was prepared from 80.3following the procedure described in the synthesis of I-1. The productwas purified by preparative HPLC. MS (ES): m/z: 499.41 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.50 (s, 1H), 8.93-8.92 (d, J=2.8 Hz, 1H), 8.49(s, 1H), 8.34-8.33 (d, J=2.4 Hz, 1H), 8.16-8.14 (d, J=5.6 Hz, 1H),7.80-7.79 (d, J=2.4 Hz, 1H), 7.77-7.76 (d, J=1.6 Hz, 1H), 7.66 (s, 1H),7.55-7.53 (d, J=8.8 Hz, 1H), 7.38-7.37 (d, J=2.4 Hz, 1H), 6.92-6.89 (m,1H), 6.63-6.61 (m, 1H), 6.55-6.54 (m, 1H), 5.27-5.23 (m, 1H), 3.74 (s,3H), 2.02 (s, 3H), 1.45-1.44 (d, 6H).

Example 81:N-(4-((2-((1-isopropyl-2-oxo-5-(1H-pyrazol-1-yl)-1,2-dihydropyridin-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-81. Compound I-81 was prepared from 80.3 andInt-5 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.4% methanol in dichloromethane as eluant). MS (ES): m/z:497.99 [M−H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 1H), 8.96 (s, 1H),8.60 (s, 1H), 8.35 (s, 1H), 8.22-8.20 (d, J=5.6 Hz, 1H), 8.02-7.99 (d,J=8.4 Hz, 1H), 7.83 (s, 1H), 7.79-7.77 (d, J=6.0 Hz, 2H), 6.95-6.93 (d,J=8.0 Hz, 1H), 6.77-6.76 (d, J=4.0 Hz, 1H), 6.55 (s, 1H), 5.26-5.23 (m,1H), 3.69 (s, 3H), 2.05 (s, 3H), 1.45-1.43 (d, 6H).

Example 82:N-(4-((2-((5-(azetidin-1-yl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 82.1. To a solution of 61.2 (0.5 g, 2.15 mmol, 1.0equiv) in toluene (50 mL) and water (5 mL) was added azetidine (0.367 g,6.45.0 mmol, 3.0 equiv), cesium carbonate (1.7 g, 5.36 mmol, 2.5 equiv).The reaction mixture was degassed by bubbling argon through for 10 min.Under argon atmosphere was added4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.124 g, 0.215 mmol,0.1 equiv) and tris(dibenzylideneacetone)dipalladium (0.098 g, 0.1075mmol, 0.05 equiv). The reaction mixture was degassed for 5 min and wasstirred at 130° C. for 1 h. It was cooled to room temperature, filteredthrough a pad of Celite®. The filtrate was poured over water, extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC to obtain82.1. MS (ES): m/z 210.21 [M+H]⁺.

Synthesis of compound 82.2. A mixture of compound 82.1 (0.040 g, 0.191mmol, 1.0 equiv), methanol (3 mL) and 10% palladium on carbon (0.020 g)was stirred at rt under 1 atm of hydrogen for 1 h. It was filteredthrough a pad of Celite® and rinsed with methanol. The filtrate wasconcentrated under reduced pressure to obtain 82.2. MS (ES): m/z 180.2[M+H]⁺.

Synthesis of compound 82.3. Compound 82.3 was prepared from 82.2following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 222.3 [M+H]⁺.

Synthesis of compound I-82. Compound I-82 was prepared from 82.3 andInt-2 following the procedure described in the synthesis of IA. Theproduct was purified by preparative HPLC. MS (ES): m/z: 460.77 [M−H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 8.12-8.11 (d, J=5.6 Hz, 1H),7.65 (s, 1H), 7.50 (s, 1H), 7.43-7.41 (d, J=7.6 Hz, 1H), 7.18-7.16 (d,J=8.4 Hz, 1H), 7.08 (s, 1H), 6.74-6.72 (d, J=7.2 Hz, 1H), 6.57-6.56 (d,J=3.6 Hz, 1H), 5.61-5.59 (d, J=7.6 Hz, 1H), 4.03-3.99 (m, 4H), 3.58 (s,3H), 3.31 (bs, 3H), 2.18-2.14 (m, 2H), 2.03 (s, 3H).

Example 83:N-(4-((2-((5-(azetidin-1-yl)-1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 83.1 To a solution of 65.1 (1.0 g, 3.83 mmol, 1.0equiv) in ethanol (10 mL) and water (2 mL), iron powder (2.14 g, 38.3mmol, 10 equiv) was added followed by ammonium chloride (2.06 g, 38.3mmol, 10 equiv). The reaction mixture was stirred at 60° C. for 3 h. Itwas filtered through a pad of Celite® and rinsed with ethanol. Thefiltrate was concentrated under reduced pressure and the residue waspurified by flash column chromatography on silica gel (CombiFlash®, 30%ethyl acetate in hexane as eluant) to afford 83.1. MS (ES): m/z 232.1[M+H]⁺.

Synthesis of compound 83.2. To a solution of 83.1 (0.725 g, 3.14 mmol,1.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was added sodiumbicarbonate (1.055 g, 12.56 mmol, 4.0 equiv) followed by benzylchloroformate (2.66 g, 15.7 mmol, 5.0 equiv). The reaction mixture wasstirred at room temperature for 16 h. It was poured over water,extracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 20% ethyl acetate inhexane as eluant) to afford 83.2. MS (ES): m/z 366.2 [M+H]⁺.

Synthesis of compound 83.3. To a solution of 83.2 (0.55 g, 1.51 mmol,1.0 equiv) in toluene (10 mL) was added azetidine (0.429 g, 7.53 mmol,5.0 equiv) and sodium tert-butoxide (0.289 g, 3.02 mmol, 2.0 equiv). Thereaction mixture was degassed by bubbling argon through for 10 min andwas added (2-biphenyl)di-tert-butylphosphine (0.044 g, 0.151 mmol, 0.1equiv) and palladium acetate (0.016 g, 0.075 mmol, 0.05 equiv). It wasdegassed for 5 min. The reaction mixture was stirred at 100° C. for 15min. It was cooled to room temperature, filtered through a pad ofCelite®. The filtrate was poured over water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 30% ethyl acetate in hexane as eluant) toafford 83.3. MS (ES): m/z 342.4 [M+H]⁺.

Synthesis of compound 83.4. A mixture of compound 83.3 (0.090 g, 0.263mmol, 1.0 equiv), methanol (2 mL) and 10% palladium on carbon (0.045 g)was stirred at rt under 1 atm hydrogen for 15 min. It was filteredthrough a pad of Celite® and rinsed with methanol. The filtrate wasconcentrated under reduced pressure to obtain 83.4. MS (ES): m/z 208.3[M+H]⁺.

Synthesis of compound 83.5. Compound 83.5 was prepared from 83.5following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 250.3 [M+H]⁺.

Synthesis of compound I-83. Compound I-83 was prepared from 83.5 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by preparative HPLC. MS (ES): m/z: 488.46 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.49 (s, 1H), 8.13-8.12 (d, J=5.2 Hz, 1H),7.66 (s, 1H), 7.48 (bs, 2H), 7.20 (s, 1H), 7.10 (s, 1H), 6.75 (s, 1H),6.58 (s, 1H), 5.68 (bs, 1H), 4.98-4.94 (m, 1H), 4.03 (bs, 4H), 3.60 (s,3H), 2.17 (s, 2H), 2.04 (s, 3H), 1.25-1.24 (d, 6H).

Example 84:N-(4-((2-((6-cyclopropyl-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 84.2. To a solution of 84.1 (0.9 g, 5.49 mmol, 1.0equiv) in THF (20 mL) was added sodium hydride (0.579 g, 12.07 mmol, 2.2q) at 0° C. and stirred for 10 min. Pivaloyl chloride (0.7 mL, 5.76mmol, 1.05 equiv) was added dropwise. The reaction mixture was stirredat room temperature for 15 min. It was poured over ice-water, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain 84.2. MS (ES): m/z 230.6[M+H]⁺.

Synthesis of compound 84.3. A solution of 84.2 (1.1 g, 4.43 mmol, 1.0equiv) in acetic acid (10 mL) was stirred at 110° C. for 3 h. It waspoured over ice, stirred and neutralized with saturated sodiumbicarbonate solution. Precipitated solid was filtered out and dried wellto obtain 84.3. MS (ES): m/z 271.3 [M+H]⁺.

Synthesis of compound 84.4. To a solution of 84.3 (0.7 g, 3.05 mmol, 1.0equiv) in DMF (7 mL) was added potassium carbonate (0.841 g, 6.1 mmol,2.0 equiv) at room temperature and stirred for 15 min followed byaddition of methyl iodide (0.519 g, 3.66 mmol, 1.2 equiv). The reactionmixture was stirred at room temperature for 16 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bytrituration with n-pentane to obtain 84.4. MS (ES): m/z 244.6 [M+H]⁺.

Synthesis of compound 84.5. To a solution of 84.4 (0.350 g, 1.44 mmol,1.0 equiv) in dimethylacetamide (2 mL), water (1 mL) and ethanol (0.7mL) was added cyclopropylboronic acid (0.27 g, 3.16 mmol, 2.2 equiv),cesium carbonate (0.938 g, 2.88 mmol, 2.0 equiv) anddichlorobis(triphenylphosphine) palladium (II) (0.090 g, 0.129 mmol,0.09 equiv). The reaction mixture was heated in MW at 150° C. for 30min. It was cooled to room temperature, filtered through Celite®.Filtrate was poured over water, extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 10% ethyl acetate in hexane as eluant) to afford 84.5. MS(ES): m/z 250.3 [M+H]⁺.

Synthesis of compound 84.6. To a solution of 84.5 (0.155 g, 0.621 mmol,1.0 equiv) in methanol (2.5 mL) was added sodium methoxide solution (25%in methanol, 0.4 mL, 1.86 mmol, 3.0 equiv). The reaction mixture wasstirred at 65° C. for 2 h. Most solvent was removed under reducedpressure and the residue was poured over water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 84.6. MS (ES): m/z 166.2 [M+H]⁺.

Synthesis of compound 84.7. Compound 84.7 was prepared from 84.6following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 208.3 [M+H]⁺.

Synthesis of compound I-84. Compound I-84 was prepared from 84.7 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.2% methanol in dichloromethane as eluant). MS (ES): m/z:446.35 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1H), 8.96 (s, 1H),8.16-8.14 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.62-7.60 (d,J=8.4 Hz, 1H), 7.41 (s, 1H), 6.96-6.94 (d, J=8.4 Hz, 1H), 6.64-6.63 (d,J=3.2 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.02 (s, 3H), 1.19-1.16 (m,1H), 0.94 (bs, 2H), 0.81 (bs, 2H).

Example 85:N-(4-((2-((6-cyclopropyl-2-isopropyl-3-oxo-2,3-dihydropyridazin-4-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 85.1. To a solution of 84.3 (1.0 g, 4.35 mmol, 1.0equiv) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.7 mmol,2.0 equiv) at room temperature and stirred for 15 min followed byaddition of isopropyl bromide (0.642 g, 5.22 mmol, 1.2 equiv). Thereaction mixture was stirred at room temperature for 16 h. It was pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by trituration with n-pentane to obtain 85.1. MS (ES): m/z272.7 [M+H]⁺.

Synthesis of compound 85.2. Compound 85.2 was prepared from 85.1following the procedure described in the synthesis of 84.5. The productwas purified by flash column chromatography on silica gel (CombiFlash®,12% ethyl acetate in hexane as eluant). MS (ES): m/z 278.4 [M+H]⁺.

Synthesis of compound 85.3. Compound 85.3 was prepared from 85.2following the procedure described in the synthesis of 84.6. MS (ES): m/z194.2 [M+H]⁺.

Synthesis of compound 85.4. Compound 85.4 was prepared from 85.3following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 236.3 [M+H]⁺.

Synthesis of compound I-85. Compound I-85 was prepared from 85.4 andInt-2 following the procedure described in the synthesis of I-1. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 2.4% methanol in dichloromethane as eluant). MS (ES): m/z:475.06 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.52 (s, 1H), 8.93 (s, 1H),8.17-8.16 (d, J=6.0 Hz, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.62-7.60 (d,J=8.4 Hz, 1H), 7.42 (s, 1H), 6.97-6.95 (m, 1H), 6.65-6.63 (m, 1H),5.24-5.18 (m, 1H), 3.75 (s, 3H), 2.03 (s, 3H), 2.00-1.98 (m, 1H),1.33-1.31 (d, 6H), 0.97-0.95 (m, 2H), 0.85-0.83 (m, 2H).

Example 86:N-(4-((2-((6-cyclopropyl-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-86. Compound I-86 was prepared from 84.7 andInt-5 following the procedure described in the synthesis of I-1. Theproduct was purified by trituration with methanol:diethyl ether (1:1).MS (ES): m/z: 447.81 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 1H),9.05 (s, 1H), 8.23-8.21 (d, J=5.6 Hz, 1H), 8.09-8.07 (d, J=8.4 Hz, 1H),8.02 (s, 1H), 7.80 (s, 1H), 7.00-6.98 (d, J=8.4 Hz, 1H), 6.79-6.77 (m,1H) 3.69 (s, 3H), 2.50 (s, 3H), 2.05 (s, 3H), 2.00-1.95 (m, 1H),0.97-0.92 (m, 2H), 0.83-0.82 (m, 2H).

Example 87:(R)—N-(4-((2-((6-cyclopropyl-2-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((6-cyclopropyl-2-((5,5-dimethyltetrahydrofuran-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 87.2. To a solution of 87.1 (4.0 g, 30.28 mmol,1.0 equiv) in THF (40 mL) was added lithium diisopropylamide (2 M inTHF, 18.15 mL, 36.3 mmol, 1.2 equiv) at −78° C. and stirred for 15 minfollowed by addition of 3-bromo-2-methylprop-1-ene (4.8 g, 36.3 mmol,1.2 equiv). The reaction mixture was stirred at room temperature for 12h. It was poured over 3 N hydrochloric acid solution, stirred andextracted with diethyl ether. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain crude which was purifiedby flash column chromatography on silica gel (CombiFlash®, 2.5% ethylacetate in hexane as eluant) to afford 87.2. MS (ES): m/z 187.2 [M+H]⁺.

Synthesis of compound 87.3. To a solution of 87.2 (2 g, 10.74 mmol, 1.0equiv) in THF (40 mL) was added a solution of lithium aluminum hydride(1 M in THF, 21.5 mL, 21.48 mmol, 2.0 equiv) at 0° C. The reactionmixture was heated to reflux for 2 h. It was cooled to 0° C. and wascarefully added ice-water (2 mL) and 15% sodium hydroxide (2 mL). Thesuspension was filtered through a pad of Celite® and rinsed with diethylether. The filtrate was separated by a separatory funnel. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 50% ethyl acetate in hexaneas eluant) to 87.3. MS (ES): m/z 131.2 [M+H]⁺.

Synthesis of compound (±)-87.4. To a solution of 87.3 (1.2 g, 9.22 mmol,1.0 equiv) in 1,2-dichloroethane (12 mL) was added silvertrifluoromethanesulfonate (0.118 g, 0.461 mmol, 0.05 equiv). Thereaction mixture was stirred at 85° C. for 12 h in dark. It was filteredthrough a pad of Celite® and rinsed with ethyl acetate. The filtrate wasseparated by a separatory funnel. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 45% ethyl acetate in hexane as eluant) to(±)-87.4. MS (ES): m/z 131.2 [M+H]⁺.

Synthesis of compound (±)-87.5. To a solution of (±)-87.4 (0.810 g, 6.22mmol, 1.0 equiv) and triethylamine (2.16 mL, 15.55 mmol, 2.5 equiv) indichloromethane (10 mL) was added methanesulfonyl chloride (0.72 mL,9.33 mmol, 1.5 equiv) at 0° C. and stirred at room temperature for 12 h.It was poured over ice, stirred and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain (±)-87.5. MS (ES): m/z 209.3 [M+H]⁺.

Synthesis of compound (±)-87.6. To a solution of 84.3 (0.750 g, 3.27mmol, 1.0 equiv) in DMF (15 mL) was added cesium carbonate (2.66 g, 8.17mmol, 2.5 equiv) at room temperature and stirred for 15 min followed byaddition of (±)-87.5 (0.816 g, 3.92 mmol, 1.2 equiv). The reactionmixture was stirred at 70° C. for 3 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bytrituration with n-pentane to obtain (±)-87.6. MS (ES): m/z 342.8[M+H]⁺.

Synthesis of compound (±)-87.7. Compound (±)-87.7 was prepared from(±)-87.6 following the procedure described in the synthesis of 84.5. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 12% ethyl acetate in hexane as eluant). MS (ES): m/z 348.5[M+H]⁺.

Synthesis of compound (±)-87.8. Compound (±)-87.8 was prepared from(±)-87.7 following the procedure described in the synthesis of 84.6. MS(ES): m/z 264.3 [M+H]⁺.

Synthesis of compound (±)-87.9. Compound (±)-87.9 was prepared from(±)-87.8 following the procedure described in the synthesis of 11.8. Thecrude product was used in the next step without further purification. MS(ES): m/z 306.4 [M+H]⁺.

Synthesis of compound (±)-I-87. Compound (±)-I-87 was prepared from(±)-87.9 following the procedure described in the synthesis of I-1. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3.0% methanol in dichloromethane as eluant). MS (ES): m/z:544.6 [M+H]⁺.

I-87-a and I-87-b. Compound (±)-I-87 was separated on HPLC (column:CHIRALCEL OX-H (250 mm×21.0 mm, 5 μm); mobile phases: (A) 0.1%diethylamine in hexane (B) 0.1% diethylamine in 2-propanol:methanol(50:50); flow rate: 19 mL/min) to afford first eluting fraction (I-87-a)and second eluting fraction (I-87-b). (*Absolute stereochemistry notdetermined.)

I-87-a. MS (ES): m/z: 544.4 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.52(s, 1H), 8.97 (s, 1H), 8.17-8.16 (d, J=6.0 Hz, 1H), 8.01 (s, 1H), 7.66(s, 1H), 7.62-7.60 (d, J=8.4 Hz, 1H), 7.42 (bs, 1H), 6.98-6.95 (m, 1H),6.65-6.63 (m, 1H), 4.20-4.15 (m, 1H), 4.10-4.05 (m, 1H), 3.82-3.78 (m,1H), 3.75 (s, 3H), 2.86-2.82 (m, 1H), 2.02 (s, 3H), 2.00-1.96 (m, 2H),1.87-1.81 (m, 1H), 1.56-1.51 (m, 1H), 1.26 (s, 6H), 0.97-0.94 (m, 2H),0.86-0.82 (m, 2H).

I-87-b. MS (ES): m/z: 544.5 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51(s, 1H), 8.97 (s, 1H), 8.17-8.16 (d, J=6.0 Hz, 1H), 8.00 (s, 1H), 7.65(s, 1H), 7.62-7.59 (d, J=8.4 Hz, 1H), 7.41 (bs, 1H), 6.97-6.94 (m, 1H),6.64-6.62 (m, 1H), 4.18-4.15 (m, 1H), 4.10-4.05 (m, 1H), 3.81-3.77 (m,1H), 3.75 (s, 3H), 2.85-2.82 (m, 1H), 2.02 (s, 3H), 2.00-1.96 (m, 2H),1.87-1.81 (m, 1H), 1.56-1.51 (m, 1H), 1.26 (s, 6H), 0.97-0.94 (m, 2H),0.86-0.82 (m, 2H).

Example 88:N-(4-((2-((5-cyclopropyl-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridazin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 88.2. To a solution of 88.1 (2.0 g, 12.98 mmol,1.0 equiv) in acetic acid (40 mL) was added potassium acetate (4.57 g,46.72 mmol, 3.6 equiv) followed by addition of bromine (4.56 g, 28.55mmol, 2.2 equiv). The reaction mixture was stirred at 80° C. for 6-7 h.It was poured over water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.1% methanol in dichloromethane) to afford 88.2. MS (ES): m/z 234.1[M+H]⁺.

Synthesis of compound 88.3. To a solution of 88.2 (1.2 g, 5.15 mmol, 1.0equiv) in DMF (10 mL) was added cesium carbonate (3.34 g, 10.3 mmol, 2.0equiv) and stirred for 15 min. To the mixture was added4-bromotetrahydro-2H-pyran (1.7 g, 10.3 mmol, 2.0 equiv). The reactionmixture was stirred at 80° C. for 16 h. It was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 30% ethyl acetate inhexane as eluant) to afford 88.3. MS (ES): m/z 318.2 [M+H]⁺.

Synthesis of compound 88.4. To a solution of 88.3 (0.700 g, 2.21 mmol,1.0 equiv) in toluene (10 mL) and water (1 mL) was addedcyclopropylboronic acid (0.568 g, 6.62 mmol, 3.0 equiv), potassiumcarbonate (0.609 g, 4.42 mmol, 2.0 equiv) and tricyclohexylphosphine(0.123 g, 0.442 mmol, 0.2 equiv). The reaction mixture was degassed for10 min under argon atmosphere then palladium(II) acetate (0.039 g, 0.176mmol, 0.08 equiv) was added, again degassed for 5 min. The reactionmixture was stirred at 100° C. for 1-2 h. It was cooled to roomtemperature, filtered through a pad of Celite®. The filtrate was pouredover water, extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 35% ethylacetate in hexane as eluant) to afford 88.4. MS (ES): m/z 279.3 [M+H]⁺.

Synthesis of compound 88.5. To a solution of 88.4 (0.275 g, 0.988 mmol,1.0 equiv) in THF:methanol:water (10 mL, 2:1:1) was added lithiumhydroxide (0.207 g, 4.94 mmol, 5.0 equiv). The reaction stirred at roomtemperature for 16 h. It was concentrated under reduced pressure toobtain residue. To the mixture was added water and acidified with 1 Nhydrochloric acid to adjust pH-3. It was extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toobtain 88.5. MS (ES): m/z 265.3 [M+H]⁺.

Synthesis of compound 88.6. To a solution of 88.5 (0.210 g, 0.794 mmol,1.0 equiv) in tert-butanol (5 mL) was added triethylamine (0.33 mL, 2.38mmol, 3.0 equiv) and diphenylphosphorylazide (0.436 g, 1.58 mmol, 2.0equiv) under nitrogen. The mixture was stirred at 80° C. for 3-4 h. Itcooled to room temperature, poured over water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 50% ethyl acetate in hexane) to afford 88.6. MS(ES): m/z 336.4 [M+H]⁺.

Synthesis of compound 88.7. To a solution of 88.6 (0.110 g, 0.327 mmol,1.0 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5mL) dropwise at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. It was poured over saturated aqueous solution ofsodium bicarbonate and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to obtain88.7. MS (ES): m/z 236.3 [M+H]⁺.

Synthesis of compound 88.8. Compound 88.8 was prepared from 88.7following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS (ES):m/z 278.3 [M+H]⁺.

Synthesis of compound I-88. Compound I-88 was prepared from 88.8 andInt-2 following the procedure described in the synthesis of I-1. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4% methanol in dichloromethane as eluant). MS (ES): m/z:516.8 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1H), 9.57 (s, 1H),8.16-8.15 (d, J=5.6 Hz, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.39-7.37 (d,J=8.4 Hz, 1H), 7.30 (s, 1H), 6.89-6.87 (m, 1H), 6.64-6.63 (m, 1H),5.08-4.97 (m, 1H), 4.04-3.96 (m, 2H), 3.65 (bs, 2H), 3.46 (s, 3H),2.18-2.16 (m, 2H), 2.02 (s, 3H), 1.99-1.98 (m, 1H), 1.78-1.69 (m, 2H),1.05-1.01 (m, 2H), 0.82 (bs, 2H).

Example 89:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 89.2. To a 1 M aqueous solution of sodiumhydroxide (51 mL, 135 mmol, 1.0 equiv) at 0° C. was added 89.1 (15 g,135 mmol, 1.0 equiv). After 15 min dimethyl sulfate (12.8 mL, 135 mmol,1.0 equiv) was added at 0° C. The reaction mixture was stirred at roomtemperature for 3 h. It was neutralized with acetic acid to pH 7 andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.2% methanol indichloromethane as eluant) to afford 89.2. MS (ES): m/z 126.2 [M+H]⁺.

Synthesis of compound 89.3. To a solution of 89.2 (4.0 g, 31.97 mmol,1.0 equiv) in dichloromethane (40 mL) was added N-bromosuccinimide (6.79g, 38.36 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred atroom temperature for 30 min. It was poured over ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3% methanol indichloromethane as eluant) to afford 89.3. MS (ES): m/z 205.1 [M+H]⁺.

Synthesis of compound 89.4. To a solution of 89.3 (3.0 g, 14.7 mmol, 1.0equiv) in DMF (30 mL) was added potassium carbonate (4.46 g, 32.34 mmol,2.2 equiv) and stirred at room temperature for 15 min. To the mixturewas added methyl iodide (1.04 mL, 16.17 mmol, 1.1 equiv). The reactionmixture was stirred at room temperature for 30 min. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.2% methanol in dichloromethane as eluant) to afford 89.4. MS (ES): m/z219.1 [M+H]⁺.

Synthesis of compound 89.5. Compound 89.5 was prepared from 89.4following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.5% methanol in dichloromethane as eluant). MS (ES): m/z 180.2 [M+H]⁺.

Synthesis of compound 89.6. To a solution of 89.5 (0.675 g, 3.77 mmol,1.0 equiv) in dichloromethane (10 mL) was added boron tribromide (0.73mL, 7.54 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred for30 min. It was poured over saturated sodium bicarbonate solution,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 3.5% methanol indichloromethane as eluant) to afford 89.6. MS (ES): m/z 166.2 [M+H]⁺.

Synthesis of compound 89.7. To a solution of Int-2 (0.300 g, 1.10 mmol,1.0 equiv) in THF (3 mL) was added 1,1′-carbonyldiimidazole (0.213 g,1.32 mmol, 1.2 equiv). The reaction mixture was stirred at 70° C. for 3h. It was cooled to room temperature and concentrated under reducedpressure. This was further triturated with hexane to obtain 89.7. MS(ES): m/z: 299.3 [M+H]⁺.

Synthesis of compound 89.8. Compound 89.7 (0.220 g, 0.737 mmol, 1.0equiv) in phosphoryl chloride (5 mL) was stirred at 100° C. for 4 h. Itwas cooled and poured over saturated sodium bicarbonate solution,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 2.6% methanol indichloromethane as eluant) to afford 89.8. MS (ES): m/z 317.7 [M+H]⁺.

Synthesis of I-89. A mixture of 89.8 (0.065 g, 0.205 mmol, 1.0 equiv),89.6 (0.051 g, 0.307 mmol, 1.5 equiv) and potassium carbonate (0.056 g,0.41 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 90° C. for 16 h. Itwas cooled to room temperature, poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2.4% methanol in dichloromethane as eluant). MS(ES): m/z: 446.35 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): 10.52 (s, 1H),8.16-8.15 (d, J=6.0 Hz, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 7.44-7.40 (m,3H), 6.93-6.88 (m, 1H), 6.63-6.62 (d, J=6.0 Hz, 1H), 3.69 (s, 3H), 3.46(s, 3H), 2.04 (s, 3H), 1.79 (bs, 1H), 0.86-0.84 (m, 2H), 0.63-0.62 (m,2H).

Example 90:N-(4-((2-((5-cyclopropyl-1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 90.1. To a solution of 89.3 (2.0 g, 9.8 mmol, 1.0equiv) in dimethoxyethane (20 mL) was added cesium carbonate (7.96 g,24.5 mmol, 2.5 equiv) and stirred at room temperature for 15 min. To themixture was added 2-bromopropane (2.41 g, 19.61 mmol, 1.5 equiv). Thereaction mixture was stirred at 80° C. for 16 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.1% methanol in dichloromethane as eluant) to afford 90.1. MS (ES): m/z247.1 [M+H]⁺.

Synthesis of compound 90.2. Compound 90.2 was prepared from 90.1following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.5% methanol in dichloromethane as eluant). MS (ES): m/z 180.2 [M+H]⁺.

Synthesis of compound 90.3. To a solution of 90.2 (0.950 g, 4.58 mmol,1.0 equiv) in dichloromethane (10 mL) was added boron tribromide (0.88mL, 9.16 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred for30 min. It was poured over saturated sodium bicarbonate solution,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 1.5% methanol indichloromethane as eluant) to afford 90.3. MS (ES): m/z 194.3 [M+H]⁺.

Synthesis of compound I-90. A mixture of 89.8 (0.065 g, 0.205 mmol, 1.0equiv), 90.3 (0.059 g, 0.307 mmol, 1.5 equiv) and potassium carbonate(0.056 g, 0.41 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 90° C. for16 h. It was cooled to room temperature, poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.2% methanol indichloromethane as eluant) to afford I-90. MS (ES): m/z: 474.40 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.52 (s, 1H), 8.16-8.15 (d, J=6.0 Hz, 1H),7.65 (s, 1H), 7.58 (s, 1H), 7.43-7.39 (m, 2H), 7.34-7.33 (d, J=2.0 Hz,1H), 6.94-6.91 (m, 1H), 6.63-6.61 (m, 1H), 5.02 (s, 1H), 3.69 (s, 3H),2.04 (s, 3H), 1.90-1.87 (m, 1H), 1.33-1.32 (d, 6H), 0.87-0.85 (m, 2H),0.66-0.65 (m, 2H).

Example 91:N-(4-((1-methyl-2-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 91.3. A mixture of 91.2 (1.0 g, 3.45 mmol, 1.0equiv), potassium carbonate (0.952 g, 6.9 mmol, 2.0 equiv) and 91.1(0.647 g, 5.17 mmol, 1.5 equiv) in DMF (10 mL) was stirred at 90° C. for16 h. It was poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 0.8% methanol in dichloromethane as eluant) to afford91.3. MS (ES): m/z 335.2 [M+H]⁺.

Synthesis of compound 91.4. To a solution of 91.3 (0.500 g, 1.50 mmol,1.0 equiv) in dimethyl sulfoxide (5 mL) was added bis(pinacolato)diboron(0.571 g, 2.25 mmol, 1.5 equiv), potassium acetate (0.441 g, 4.5 mmol,3.0 equiv) and tricyclohexylphosphine (0.084 g, 0.3 mmol, 0.2 equiv).The reaction mixture was degassed for 10 min under argon atmosphere thenpalladium(II) acetate (0.034 g, 0.15 mmol, 0.1 equiv) was added, againdegassed for 5 min. The reaction mixture was stirred at 100° C. for 2 h.It was cooled to room temperature, filtered through a pad of Celite®.The filtrate was poured over water, extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 1.0% methanol in dichloromethane as eluant) to afford91.4. MS (ES): m/z 382.2 [M+H]⁺.

Synthesis of compound 91.5. To a solution of 91.4 (0.335 g, 0.878 mmol,1.0 equiv) in DMF (3 mL) was added hydrogen peroxide solution (30%, 0.25mL, 2.19 mmol, 2.5 equiv). The reaction mixture was stirred at roomtemperature for 48 h. It was poured over water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1.5% methanol in dichloromethane as eluant) toafford 91.5. MS (ES): m/z 272.3 [M+H]⁺.

Synthesis of I-91. A mixture of 91.5 (0.150 g, 0.552 mmol, 1.0 equiv),91.6 (0.094 g, 0.552 mmol, 1.0 equiv) and cesium carbonate (0.448 g,1.38 mmol, 2.5 equiv) in DMF (3 mL) was stirred at 150° C. in amicrowave reactor for 2 h. It was cooled to room temperature, pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 2.4%methanol in dichloromethane as eluant) to afford material which wasfurther purified by prep HPLC to obtain I-91. MS (ES): m/z: 406.21[M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.51 (s, 1H), 8.15 (s, 1H), 7.72(bs, 1H), 7.64 (bs, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 6.93(bs, 1H), 6.61 (bs, 1H), 6.31 (bs, 1H), 3.69 (s, 3H), 3.49 (s, 3H), 2.02(s, 3H).

Example 92:N-(4-((2-((5-cyclopropyl-1-((1s,3s)-3-hydroxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 92.2. To a solution of 92.1 (5 g, 28.37 mmol, 1.0equiv) in methanol (50 mL) was added sodium borohydride (1.401 g, 36.88mmol, 1.3 equiv) in small portions at 0° C. The reaction mixture wasstirred at room temperature for 3 h. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 92.2. MS (ES): m/z179.3 [M+H]⁺.

Synthesis of compound 92.3. To a mixture of compound 92.2 (3.2 g, 17.95mmol, 1.0 equiv), 4-nitrobenzoic acid (3.0 g, 17.95 mmol, 1.0 equiv) andtriphenylphosphine (5.64 g, 21.54 mmol, 1.2 equiv) in dichloromethane(30 mL) at 0° C. was added diisopropylazodicarboxylate (1.35 g, 21.54mmol, 1.2 equiv). The reaction mixture was stirred at room temperaturefor 4 h. It poured over ice-water and extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 10% ethyl acetate in hexane as eluant) to afford 92.3. MS(ES): m/z 328.3 [M+H]⁺.

Synthesis of compound 92.4. To a solution of 92.3 (2.45 g, 7.48 mmol,1.0 equiv) in methanol (25 mL) was added potassium carbonate (3.09 g,22.44 mmol, 3.0 equiv). The reaction mixture was stirred at roomtemperature for 3 h. It was poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 92.4. MS (ES): m/z 179.2 [M+H]⁺.

Synthesis of compound 92.5. To a solution of 92.4 (1.1 g, 6.17 mmol, 1.0equiv) in dichloromethane (10 mL) was added triethylamine (1.1 mL, 8.02mmol, 1.3 equiv) at 0° C. followed by addition ofmethanesulfonylchloride (0.62 mL, 8.02 mmol, 1.3 equiv). The reactionmixture was stirred at room temperature for 3 h. It was poured overice-water, stirred and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,12% ethyl acetate in hexane as eluant) to afford 92.5. MS (ES): m/z257.3 [M+H]⁺.

Synthesis of compound 92.6. To a solution of 89.3 (2.7 g, 13.23 mmol,1.0 equiv) in DMF (50 mL) was added cesium carbonate (12.93 g, 39.69mmol, 3.0 equiv) and stirred for 30 min. The reaction mixture cooled to0° C. and solution of 92.5 (4.07 g, 15.88 mmol, 1.2 equiv) in DMF (10mL) was added dropwise. The reaction mixture was stirred at 90° C. for16 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 50% ethyl acetate in hexane as eluant) toafford 92.6. MS (ES): m/z 365.2 [M+H]⁺.

Synthesis of compound 92.7. Compound 92.7 was prepared from 92.6following the procedure described in the synthesis of 61.3. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.2% methanol in dichloromethane as eluant). MS (ES): m/z 326.4 [M+H]⁺.

Synthesis of compound 92.8. To a solution of 92.7 (0.400 g, 1.23 mmol,1.0 equiv) in dichloromethane (12 mL) was added boron tribromide (0.6mL, 6.15 mmol, 5.0 equiv) at 0° C. The reaction mixture was stirred atroom temperature for 1 h. It was poured over saturated sodiumbicarbonate solution, stirred and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5.0% methanol in dichloromethane as eluant) to afford92.8. MS (ES): m/z 222.3 [M+H]⁺.

Synthesis of compound I-92. To a solution of Int-2 (0.095 g, 0.299 mmol,1.0 equiv) in DMF (2 mL) was added 92.8 (0.100 g, 0.449 mmol, 1.5 equiv)followed by potassium carbonate (0.082 g, 0.598 mmol, 2.0 equiv). Thereaction mixture was stirred at 120° C. for 3 h. It was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 10% methanolic ammonia in dichloromethane as eluant) toafford I-92. MS (ES): m/z: 502.1 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ10.51 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.64 (s, 1H), 7.61 (s, 1H),7.41-7.37 (m, 3H), 6.92-6.90 (d, J=8.4 Hz, 1H), 6.62-6.61 (d, J=3.6 Hz,1H), 5.28-5.26 (d, 1H), 4.59-4.55 (m, 1H), 3.96-3.91 (m, 1H), 3.67 (s,3H), 2.71-2.69 (d, 2H), 2.13-2.10 (d, 2H), 2.03 (s, 3H), 1.91 (bs, 1H),0.88-0.86 (m, 2H), 0.66-0.65 (m, 2H).

Example 93:N-(4-((2-((1-isopropyl-2-oxo-5-(1H-pyrazol-1-yl)-1,2-dihydropyridin-3-yl)oxy)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 93.1. To a solution of 89.3 (2.0 g, 9.8 mmol, 1.0equiv) in dimethoxyethane (20 mL) was added cesium carbonate (7.96 g,24.5 mmol, 2.5 equiv) and stirred at room temperature for 15 min. To themixture was added 2-bromopropane (2.41 g, 19.61 mmol, 1.5 equiv). Thereaction mixture was stirred at 80° C. for 16 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.1% methanol in dichloromethane as eluant) to afford 93.1. MS (ES): m/z247.1 [M+H]⁺.

Synthesis of compound 93.2. To a solution of 93.1 (1.4 g, 5.69 mmol, 1.0equiv) in 1,4-dioxane (15 mL) was added pyrazole (0.464 g, 6.83 mmol,1.2 equiv), potassium carbonate (1.96 g, 14.22 mmol, 2.5 equiv). Thereaction mixture was degassed for 10 min under argon atmosphere then1,2-dimethylethylenediamine (0.075 g, 0.85 mmol, 0.15 equiv) and copperiodide (0.326 g, 1.707 mmol, 0.3 equiv) was added, again degassed for 5min. The reaction mixture was stirred at 100° C. for 12 h. It was cooledto room temperature, poured over water, extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane as eluant) to afford93.2. MS (ES): m/z 234.3 [M+H]⁺.

Synthesis of compound 93.3. To a solution of 93.5 (0.610 g, 2.61 mmol,1.0 equiv) in dichloromethane (10 mL) was added boron tribromide (0.49mL, 5.22 mmol, 2.0 equiv) at 0° C. The reaction mixture was stirred for2 h. It was poured over saturated sodium bicarbonate solution, stirredand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.5% methanol indichloromethane as eluant) to afford 93.3. MS (ES): m/z 220.2 [M+H]⁺.

Synthesis of compound 93.4. To a solution of Int-5.3 (0.900 g, 3.29mmol, 1.0 equiv) in THF (9 mL) was added 1,1′-carbonyldiimidazole (0.638g, 3.94 mmol, 1.2 equiv). The reaction mixture was stirred at 70° C. for3 h. It was cooled to room temperature and concentrated under reducedpressure. This was further triturated with hexane to obtain 93.4. MS(ES): m/z: 300.3 [M+H]⁺.

Synthesis of compound 93.5. Compound 93.4 (0.800 g, 2.67 mmol, 1.0equiv) in phosphorylchloride (8 mL) was stirred at 100° C. for 4 h. Itwas cooled and poured over saturated sodium bicarbonate solution,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 2.8% methanol indichloromethane as eluant) to afford 93.5. MS (ES): m/z 318.7 [M+H]⁺.

Synthesis of compound I-93. A mixture of 93.8 (0.070 g, 0.220 mmol, 1.0equiv), 93.6 (0.058 g, 0.264 mmol, 1.2 equiv) and potassium carbonate(0.091 g, 0.66 mmol, 3.0 equiv) in DMF (2 mL) was stirred at 90° C. for5 h. It was cooled to room temperature, poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 4.5% methanol indichloromethane as eluant) to afford I-93. MS (ES): m/z: 501.22 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.59 (s, 1H), 8.42 (s, 1H), 8.28 (s, 1H),8.24-8.22 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.97-7.95 (d, J=8.4 Hz, 1H),7.83 (s, 1H), 7.76 (s, 1H), 7.01-6.99 (d, J=8.0 Hz, 1H), 6.80-6.79 (d,J=3.6 Hz, 1H), 5.12-5.09 (m, 1H), 3.65 (s, 3H), 3.41-3.38 (m, 1H), 2.07(s, 3H), 1.41-1.40 (d, 6H).

Example 94:N-(4-((7-cyano-2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 94.1. To a solution of Int-4 (0.200 g, 0.672 mmol,1.0 equiv) in THF (3 mL) was added 1,1′-carbonyldiimidazole (0.130 g,0.806 mmol, 1.2 equiv). The reaction mixture was stirred at 70° C. for 3h. It was cooled to room temperature and poured over ice-water.Precipitated solid was filtered out and triturated with hexane to obtain94.1. MS (ES): m/z: 324.3 [M+H]⁺.

Synthesis of compound 94.2. compound 94.1 (0.180 g, 0.556 mmol, 1.0equiv) in phosphorylchloride (5 mL) was stirred at 100° C. for 8 h. Itwas cooled and poured over saturated sodium bicarbonate solution,stirred and extracted with dichloromethane. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 1.8% methanol indichloromethane as eluant) to afford 94.2. MS (ES): m/z 342.5 [M+H]⁺.

Synthesis of compound I-94. A mixture of 94.2 (0.090 g, 0.263 mmol, 1.0equiv), 89.6 (0.108 g, 0.658 mmol, 2.5 equiv) and potassium carbonate(0.108 g, 0.789 mmol, 3.0 equiv) in DMF (3 mL) was stirred at 110° C.for 3 h. It was cooled to room temperature, poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3.0% methanol indichloromethane as eluant) to afford I-94. MS (ES): m/z: 471.5 [M+H]⁺,¹H NMR (DMSO-d6, 400 MHz): δ 10.63 (s, 1H), 8.23-8.22 (d, J=6.0 Hz, 1H),7.80-7.78 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H),7.16-7.14 (d, J=8.8 Hz, 1H), 6.74-6.72 (m, 1H), 3.93 (s, 3H), 3.46 (s,3H), 2.04 (s, 3H), 1.79 (bs, 1H), 0.86-0.84 (d, 2H), 0.62-0.61 (d, 2H).

Example 95:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-95. Compound I-95 was prepared from 93.5 and89.5 following the procedure described in the synthesis of 1-94. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.2% methanol in dichloromethane as eluant). MS (ES): m/z:447.5 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.57 (s, 1H), 8.22-8.20 (d,J=5.6 Hz, 1H), 7.92-7.90 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H),7.47 (s, 1H), 6.98-6.96 (d, J=8.0 Hz, 1H), 6.78 (bs, 1H), 3.62 (s, 3H),3.42 (s, 3H), 2.05 (s, 3H), 1.78 (bs, 1H), 0.85 (bs, 2H), 0.62 (bs, 2H).

Example 96:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 96.2 Hydrogen peroxide (30 wt. %) (31 mL) wasadded dropwise to concentrated sulfuric acid (60 mL) at 0° C. To thesolution was added a solution of 96.1 (5.0 g, 38.43 mmol, 1.0 eq) inconcentrated sulfuric acid (60 mL) dropwise at 0° C. The reactionmixture was stirred at room temperature for 48 h. It was carefullypoured over crushed ice and stirred. The aqueous mixture was basifiedwith saturated aqueous sodium bicarbonate. Precipitates were removed byfiltration and the filtrate was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 96.2. ¹H NMR (CDCl₃, 400 MHz): δ 8.35 (bs, 1H), 7.62-7.58 (m,1H).

Synthesis of compound 96.3. To a solution of 96.2 (2.3 g, 14.37 mmol,1.0 eq) in acetonitrile (20 mL) was added aqueous methylamine solution(40%) (1.1 mL, 14.37 mmol, 1.0 eq) dropwise at 0° C. The reactionmixture was stirred at room temperature for 1 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford 96.3. ¹H NMR (CDCl₃,400 MHz): δ 7.93 (bs, 1H), 7.78-7.75 (d, 1H), 7.02-6.99 (m, 1H), 3.06(s, 3H).

Synthesis of compound 96.4. A mixture of 96.3 (1.6 g, 9.35 mmol, 1.0eq), Int-1 (1.71 g, 11.22 mmol, 1.2 eq) and sodium carbonate (1.98 g,18.7 mmol, 2.0 eq) in DMF (15 mL) was stirred at 90° C. for 12 h. Thereaction mixture was cooled to room temperature, transferred intoice-water and extracted with ethyl acetate. The combined organic layerswere with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2% methanol indichloromethane) to afford 96.4. MS (ES): m/z 304.3 [M+H]⁺.

Synthesis of compound 96.5. Compound 96.5 was prepared from compound96.4 following the procedure described in the synthesis of compoundInt-2. The crude product was used in the next step without furtherpurification. MS (ES): m/z 274.3 [M+H]⁺.

Synthesis of compound 96.6. A mixture of 96.5 (0.550 g, 2.01 mmol, 1.0eq) and 1,1′-carbonyldiimidazole (1.041 g, 6.43 mmol, 3.2 eq) in THF (6mL) was stirred at 70° C. for 3 h. It was cooled to room temperature andpoured over ice-water. Precipitates were collected by filtration andtriturated with hexane to obtain 96.6. MS (ES): m/z: 300.3 [M+H]⁺.

Synthesis of compound 96.7. Compound 96.6 (0.370 g, 1.24 mmol, 1.0 eq)in phosphorylchloride (10 mL) was heated to reflux for 8 h. It wascooled to rt and slowly poured into ice-saturated sodium bicarbonatesolution, stirred and extracted with dichloromethane. The combinedorganic layers were with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 3.2%methanol in dichloromethane as eluant) to obtain 96.7. MS (ES): m/z318.7 [M+H]⁺.

Synthesis of compound I-96. A mixture of 96.7 (0.040 g, 0.125 mmol, 1.0eq), 89.6 (0.031 g, 0.188 mmol, 1.5 eq) and potassium carbonate (0.051g, 0.375 mmol, 3.0 eq) in DMF (2 mL) was stirred at 100° C. for 2 h. Itwas cooled to room temperature, poured over ice-water and extracted withethyl acetate. The combined organic layers were with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4.0% methanol in dichloromethane as eluant) toafford I-96. MS (ES): m/z: 447.19 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ10.57 (s, 1H), 8.20-8.15 (m, 2H), 7.96-7.95 (d, J=2.0 Hz, 1H), 7.67 (s,1H), 7.60 (s, 1H), 7.50 (s, 1H), 6.69-6.68 (d, 3.6 Hz, 1H), 3.73 (s,3H), 3.48 (s, 3H), 2.05 (s, 3H), 1.81 (bs, 1H), 0.87-0.86 (d, 2H),0.65-0.64 (d, 2H).

Example 97:N-(4-((2-((5-cyclopropyl-1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of Compound I-97. Compound I-97 was prepared from compound96.7 and compound 90.3 following the procedure described in thesynthesis of compound I-96. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 3.8% methanol indichloromethane as eluant). MS (ES): m/z: 475.20 [M+H]⁺, ¹H NMR(DMSO-d6, 400 MHz): δ 10.57 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 8.15(s, 1H), 7.95 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.38 (s, 1H),6.69-6.68 (d, 3.2 Hz, 1H), 5.05-5.02 (m, 1H), 3.72 (s, 3H), 2.05 (s,3H), 1.90 (bs, 1H), 1.35-1.33 (d, 6H), 0.89-0.87 (d, 2H), 0.67-0.66 (d,2H).

Example 98:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 98.2 To a solution of 3,5-difluoropyridin-2-amine(98.1, 20 g, 153.73 mmol, 1.0 equiv) in acetic acid (13.3 mL, 230.59mmol, 1.5 equiv) was added acetic anhydride (18.9 mL, 199.84 mmol, 1.3equiv) followed by ferric chloride (catalytic) at room temperature andstirred for 3 h. The reaction mixture was poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was triturated withhexane to afford 98.2. ¹H NMR (CDCl₃, 400 MHz): δ 8.16 (s, 1H), 7.73 (s,1H), 7.36-7.30 (m, 1H), 2.35 (s, 3H).

Synthesis of compound 98.3. To a solution of 98.2 (18 g, 104.57 mmol,1.0 equiv) and diisopropylamine (36.2 mL, 261.4 mmol, 2.5 equiv) in THF(200 mL) at −78° C. was added n-butyl lithium (2.5 M in hexane) (104 mL,261.4 mmol, 2.5 equiv). The reaction mixture was stirred at −78° C. for2 h and was added iodomethane (13 mL, 209.12 mmol, 2.0 equiv). Thereaction was stirred for 2 h and was quenched by the addition of 1 Nhydrochloric acid. It was warmed to room temperature and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was triturated with hexane to obtain 98.3. ¹H NMR(CDCl₃, 400 MHz): δ 10.22 (s, 1H), 8.26 (s, 1H), 2.25 (s, 3H), 2.06 (s,3H).

Synthesis of compound 98.4. To a solution of 98.3 (9.00 g, 48.35 mmol,1.0 equiv) in methanol (20 mL) was added concentrated hydrochloric acid(15 mL). The reaction mixture was refluxed for 4 h. It was concentratedunder reduced pressure. To this residue was added ice-water and pH ofthe aqueous solution was adjusted to 9-10 by the addition of 3 N sodiumhydroxide solution. The mixture is extracted with diethyl ether. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 10% ethyl acetate in hexane as eluant) to afford 98.4. ¹HNMR (CDCl₃, 400 MHz): δ 7.74 (s, 1H), 4.47 (bs, 2H), 2.24 (s, 3H).

Synthesis of compound 98.5. Hydrogen peroxide (30 wt. %) (31 mL) wasadded dropwise to concentrated sulfuric acid (60 mL) at 0° C. To thesolution was added a solution of 98.4 (4.5 g, 31.22 mmol, 1.0 equiv) inconcentrated sulfuric acid (60 mL) drop wise at 0° C. The reactionmixture was stirred at room temperature for 48 h. It was carefullypoured over crushed ice, stirred and basified with saturated sodiumbicarbonate. Insoluble solids was removed by filtration and the filtratewas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 6% ethyl acetate inhexane as eluant) to afford 98.5. ¹H NMR (CDCl₃, 400 MHz): δ 8.54 (bs,1H), 2.35 (s, 3H).

Synthesis of compound 98.6. To a solution of 98.5 (0.480 g, 2.76 mmol,1.0 equiv) in acetonitrile (5 mL) was added aqueous methylamine solution(40%) (0.2 mL, 2.76 mmol, 1.0 equiv) dropwise at 0° C. The reactionmixture was stirred at room temperature for 4 h. It was poured overice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to obtain 98.6. ¹H NMR (CDCl₃,400 MHz): δ 7.82 (s, 1H), 7.21 (bs, 1H), 3.13 (s, 3H), 2.41 (s, 3H).

Synthesis of compound 98.7. A mixture of 98.6 (0.43 g, 2.32 mmol, 1.0equiv), Int-1 (0.424 g, 2.79 mmol, 1.2 equiv) and sodium carbonate(0.491 g, 4.64 mmol, 2.0 equiv) in N, N-dimethylformamide (5 mL) wasstirred at 60° C. for 12 h. The reaction mixture was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 60% ethyl acetate in hexane) to afford 98.7. MS (ES): m/z318.3 [M+H]⁺.

Synthesis of compound 98.8. A mixture of compound 98.7 (0.320 g, 1.01mmol, 1.0 equiv), 10% palladium on carbon (0.300 g), methanol (1 mL) andTHF (4 mL) was stirred at rt under 1 atm hydrogen for 3 h. The reactionmixture was filtered through a pad of Celite® and rinsed with methanol.The filtrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 4%methanol in dichloromethane as eluant) to afford 98.8 (0.210 g, 72.47%).MS (ES): m/z 288.4 [M+H]⁺.

Synthesis of compound 98.9. A solution of 98.8 (0.210 g, 0.730 mmol, 1.0equiv) and 61.5 (0.150 g, 0.730 mmol, 1.0 equiv) in 1,4-dioxane (2 mL)was stirred at 110° C. for 2 h. The reaction mixture was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4.2% methanol in dichloromethane as eluant) to afford98.9. MS (ES): m/z 494.6 [M+H]⁺.

Synthesis of I-98. To a solution of 98.9 (0.154 g, 0.312 mmol, 1.0equiv) in THF (2 mL) was added sodium hydride (0.124 g, 3.12 mmol, 10equiv). The reaction mixture was stirred at 80° C. for 36 h. Thereaction mixture was cooled to room temperature, poured over ice-waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 4.0% methanol indichloromethane as eluant) to afford I-98. MS (ES): m/z: 460.25 [M+H]⁺;¹H NMR (DMSO-d6, 400 MHz): δ 10.54 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H),8.17 (bs, 1H), 8.00 (s, 1H), 7.62 (bs, 1H), 7.21 (bs, 1H), 6.60 (s, 1H),3.90 (s, 3H), 3.56 (s, 3H), 2.45 (s, 3H), 2.04 (s, 3H), 1.83 (bs, 1H),0.87 (bs, 2H), 0.60 (bs, 2H).

Example 99:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 99.1. Compound 99.1 was prepared from compound96.5 and 20.2 following the procedure described in the synthesis ofcompound 98.9. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.8% methanol in dichloromethane as eluant).MS (ES): m/z 525.6 [M+H]⁺.

Synthesis of I-99. Compound I-99 was prepared from compound 99.1following the procedure described in the synthesis of compound I-98. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.6% methanol in dichloromethane as eluant). MS (ES): m/z:491.28 [M+H]⁺; ¹H NMR (DMSO-d6, 400 MHz): δ 10.55 (s, 1H), 9.91 (s, 1H),8.19-8.17 (d, J=6 Hz, 1H), 7.97 (s, 1H), 7.66-7.64 (m, 2H), 6.67-6.66(d, J=3.6 Hz, 1H), 6.60 (s, 1H), 5.26 (bs, 1H), 4.11-4.09 (m, 2H),3.88-3.83 (m, 2H), 3.67 (s, 3H), 2.36-2.34 (m, 2H), 2.04 (s, 3H), 1.41(s, 9H).

Example 100:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 100.1 Compound 100.1 was prepared from compound96.5 and compound 24.2 following the procedure described in thesynthesis of compound 98.9. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 3.9% methanol indichloromethane as eluant). MS (ES): m/z 525.5 [M+H]⁺.

Synthesis of I-100. Compound I-100 was prepared from compound 100.1following the procedure described in the synthesis of compound I-98. Theproduct was purified by flash column chromatography on silica gel(CombiFlash®, 3.5% methanol in dichloromethane as eluant). MS (ES): m/z:491.28 [M+H]⁺, ¹H NMR (DMSO-d6, 400 MHz): δ 10.52 (s, 1H), 9.88 (s, 1H),8.17-8.16 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.66-7.63 (m, 2H), 6.66-6.65(m, 1H), 6.59 (s, 1H), 5.25 (bs, 1H), 4.10-4.09 (m, 2H), 3.85-3.82 (m,2H), 3.66 (s, 3H), 2.38-2.33 (m, 2H), 2.03 (s, 3H), 1.41 (s, 9H).

Example 101:N-(4-((2-((5-(tert-butyl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-3-yl)amino)-3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-101. Compound I-101 was prepared from compound Int-5 andcompound 31.4 following the procedure described in the synthesis ofcompound I-1. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 3.2% methanol in dichloromethane as eluant). MS(ES): m/z: 491.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.74 (s, 1H),10.56 (S, 1H), 9.05 (s, 1H), 8.21-8.19 (d, J=5.2 Hz, 1H), 7.77-7.75 (m,2H), 7.47-7.45 (d, J=8.0 Hz, 1H), 6.13 (s, 1H), 4.61-4.58 (m, 2H),4.49-4.43 (m, 2H), 3.60 (bs, 2H), 3.37 (s, 3H), 2.05 (s, 3H), 1.25 (s,9H), 1.11-1.07 (m, 1H).

Example 102:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)oxy)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 102.1. A solution of 98.8 (0.162 g, 0.563 mmol,1.0 equiv) and 1,1′-thiocarbonyldiimidazole (0.501 g, 2.815 mmol, 5.0equiv) in THF (3 mL) was stirred at 70° C. for 16 h. The reactionmixture was cooled to room temperature and poured over ice-water.Precipitated solids were collected by filtration and air dried. Thesolids were triturated with hexane to afford 102.1. MS (ES): m/z: 330.3[M+H]⁺.

Synthesis of compound 102.2. Compound 102.1 (0.086 g, 0.261 mmol, 1.0equiv) was added to sulfuryl chloride (0.7 mL, 9.135 mmol, 35 equiv) at0° C. and stirred for 10 min. The reaction mixture was slowly pouredinto a saturated aqueous sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.4% methanol indichloromethane) to afford 102.2. MS (ES): m/z 332.5 [M+H]⁺.

Synthesis of I-102. Compound I-102 was prepared from compound 102.2 andcompound 89.6 following the procedure described in the synthesis ofcompound I-96. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.8% methanol in dichloromethane). MS (ES):m/z: 461.39 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56 (s, 1H),8.17-8.15 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.60 (bs, 2H), 7.21 (bs, 1H),6.60 (bs, 1H), 3.92 (s, 3H), 3.47 (s, 3H), 2.46 (s, 3H), 2.03 (s, 3H),1.83 (bs, 1H), 0.86 (bs, 2H), 0.64 (bs, 2H).

Example 103:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 103.1. A mixture of 96.5 (0.120 g, 0.439 mmol, 1.0equiv) and 61.5 (0.091 g, 0.439 mmol, 1.0 equiv) in 1,4-dioxane (2 mL)was stirred at 70° C. for 5 h. It was cooled to room temperature, pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine solution, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,3.2% methanol in dichloromethane) to afford 103.1. MS (ES): m/z 480.5[M+H]⁺.

Synthesis of I-103. To a solution of 103.1 (0.076 g, 0.158 mmol, 1.0equiv) in THF (2 mL) was added sodium hydride (0.031 g, 0.79 mmol, 5.0equiv). The reaction mixture was stirred at 90° C. for 4 h. It wascooled to room temperature, poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brinesolution, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 3.4% methanol indichloromethane) to afford I-103. MS (ES): m/z: 446.0 [M+H]⁺, ¹H NMR(CDCl₃/MeOD, 400 MHz): δ 8.54 (bs, 1H), 8.08 (bs, 1H), 8.03 (bs, 1H),7.78 (bs, 1H), 7.28 (s, 1H), 7.24 (bs, 1H), 6.80 (s, 1H), 6.54 (bs, 1H),3.68 (s, 3H), 3.60 (s, 3H), 2.13 (s, 3H), 1.77-1.74 (m, 1H), 0.87-0.85(m, 2H), 0.63 (bs, 2H).

Example 104:N-(4-((2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-c]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 104.1. A mixture of 96.5 (0.120 g, 0.439 mmol, 1.0equiv) and 40.8 (0.091 g, 0.439 mmol, 1.0 equiv) in 1,4-dioxane (2 mL)was stirred at 90° C. for 3 h. It was cooled to room temperature, pouredover ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine solution, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,2.3% methanol in dichloromethane) to afford 104.1. MS (ES): m/z 481.5[M+H]⁺.

Synthesis of I-104. Compound I-104 was prepared from compound 104.1following the procedure described in the synthesis of compound I-103.The product was purified by flash column chromatography on silica gel(CombiFlash®, 3.6% methanol in dichloromethane). MS (ES): m/z: 447.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.5 (s, 1H), 9.89 (s, 1H),8.18-8.16 (d, J=5.6 Hz, 1H), 7.96 (bs, 1H), 7.66 (s, 1H), 7.62 (bs, 1H),7.07 (bs, 1H), 6.83 (bs, 1H), 6.65-6.63 (m, 2H), 3.95 (s, 1H), 3.65 (bs,2H), 2.03 (s, 3H), 1.68 (bs, 2H), 1.55 (bs, 2H), 1.32 (s, 6H).

Example 105:(R)-4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)-N-methylpicolinamide

Synthesis of compound 105.1. Compound 105.1 was prepared from compound15.4 and 24.2 following the procedure described in the synthesis ofcompound 104.1. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.5% methanol in dichloromethane). MS (ES):m/z 525.6 [M+H]⁺.

Synthesis of I-105. Compound I-105 was prepared from compound 105.1following the procedure described in the synthesis of compound I-103.The product was purified by flash column chromatography on silica gel(CombiFlash®, 3.5% methanol in dichloromethane). MS (ES): m/z: 491.62[M+H]⁺, Chiral HPLC purity: 96.8%, ¹H NMR (DMSO-d6, 400 MHz): δ 9.92 (s,1H), 8.78 (s, 1H), 8.53-8.52 (d, J=5.6 Hz, 1H), 8.02-8.01 (d, J=2.4 Hz,1H), 7.69 (s, 1H), 7.40 (s, 1H), 7.20-7.19 (m, 1H), 6.61 (s, 1H), 5.29(bs, 1H), 4.10 (bs, 2H), 3.87-3.83 (m, 2H), 3.68 (s, 3H), 2.80 (s, 3H),2.27-2.24 (m, 2H), 1.42 (s, 9H).

Example 106:(S)-4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)-N-methylpicolinamide

Synthesis of I-106. Compound I-106 was prepared from compound 15.4 and20.2 following the procedure described in each step in the synthesis ofcompound I-105. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.7% methanol in dichloromethane). MS (ES):m/z: 491.32 [M+H]⁺, Chiral HPLC purity: 98%, ¹H NMR (DMSO-d₆, 400 MHz):δ 9.93 (s, 1H), 8.80-8.79 (d, J=4.4 Hz, 1H), 8.52-8.51 (d, J=5.6 Hz,1H), 8.01-8.00 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.19-7.18(m, 1H), 6.60 (s, 1H), 5.26 (bs, 1H), 4.11 (bs, 2H), 3.86-3.82 (m, 2H),3.67 (s, 3H), 2.79 (s, 3H), 2.26-2.23 (m, 2H), 1.41 (s, 9H).

Example 107:4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-benzo[d]imidazol-6-yl)oxy)-N-methylpicolinamide

Synthesis of I-107. Compound I-107 was prepared from compound 15.4 andcompound 61.4 following the procedure described in the synthesis ofcompound I-2. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES):m/z: 445.49 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 8.79-8.78 (d, J=4.4 Hz,1H), 8.52-8.50 (d, J=5.6 Hz, 1H), 8.34 (s, 1H), 8.23 (s, 1H), 7.58-7.56(d, J=8.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.16 (s, 2H), 6.95-6.93 (d, J=6.4Hz, 1H), 3.71 (s, 3H), 3.55 (s, 3H), 2.79 (d, 3H), 1.83-1.82 (m, 1H),0.88-0.86 (m, 2H), 0.61-0.60 (m, 2H).

Example 108:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-108. A mixture of 102.2 (0.032 g, 0.096 mmol, 1.0 equiv),24.1 (0.024 g, 0.115 mmol, 1.2 equiv) and potassium carbonate (0.033 g,0.24 mmol, 2.5 equiv) in 1,4-dioxane (1 mL) was degassed for 10 min bybubbling through argon. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene(0.006 g, 0.0096 mmol, 0.1 equiv) andtris(dibenzylideneacetone)dipalladium(0) (0.004 g, 0.0048 mmol, 0.05equiv) were added, and degassed for another 5 min. The reaction mixturewas stirred at 120° C. for 1 h in a sealed tube. It was cooled to roomtemperature, poured into water and extracted with ethyl acetate. Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4.2% methanol in dichloromethane). MS (ES):m/z: 505.46 [M+H]⁺, Chiral HPLC purity: 97%, ¹H NMR (DMSO-d₆, 400 MHz):10.54 (s, 1H), 9.78 (s, 1H), 8.17-8.15 (d, J=5.6 Hz, 1H), 7.89 (s, 1H),7.61 (s, 1H), 6.60-6.56 (m, 2H), 5.26 (s, 1H), 4.00 (bs, 2H), 3.83 (bs,5H), 2.41 (s, 3H), 2.34 (bs, 1H), 2.26 (bs, 1H), 2.04 (s, 3H), 1.41 (s,9H).

Example 109:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 109.1. A mixture of 96.3 (0.460 g, 2.58 mmol, 1.0equiv), 14.5 (0.441 g, 2.58 mmol, 1.0 equiv) and potassium carbonate(1.068 g, 7.74 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 80° C. for12 h. It was cooled to room temperature, poured over ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine solution, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 35-40% ethyl acetatein hexane). MS (ES): m/z 330.3 [M+H]⁺.

Synthesis of compound 109.2. Compound 109.2 was prepared from 109.1following the procedure described in the synthesis of compound Int-2.The product was purified by flash column chromatography on silica gel(CombiFlash®, 45-50% ethyl acetate in hexane). MS (ES): m/z 300.3[M+H]⁺.

Synthesis of compound 109.3. Compound 109.3 was prepared from compound109.2 and 24.2 following the procedure described in the synthesis ofcompound 104.1. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.4% methanol in dichloromethane). MS (ES):m/z 551.6 [M+H]⁺.

Synthesis of I-109. To a solution of 109.3 (0.100 g, 0.181 mmol, 1.0equiv) in THF (5 mL) was added sodium hydride (0.036 g, 0.905 mmol, 5.0equiv). The reaction mixture was stirred at 60° C. for 16 h. It wascooled to room temperature, poured over ice-water and extracted withethyl acetate. The combined organic layers were washed with brinesolution, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC toafford I-109. MS (ES): m/z: 517.20 [M+H]⁺, Chiral HPLC purity: 99%, ¹HNMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H), 9.92 (s, 1H), 8.20-8.18 (d,J=6.0 Hz, 1H), 7.96 (s, 1H), 7.64-7.63 (d, J=2.4 Hz, 2H), 6.71-6.69 (m,1H), 6.59 (s, 1H), 5.27-5.24 (m, 1H), 4.12-4.06 (m, 2H), 3.88-3.83 (m,2H), 3.67 (s, 3H), 2.39-2.34 (m, 1H), 2.28-2.20 (m, 1H), 1.41 (s, 9H),1.20-1.16 (m, 1H), 0.77-0.75 (m, 4H).

Example 110:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 110.1. Compound 110.1 was prepared from compound109.2 and 20.2 following the procedure described in the synthesis ofcompound 104.1. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.4% methanol in dichloromethane). MS (ES):m/z 551.6 [M+H]⁺.

Synthesis of I-110. Compound I-110 was prepared from compound 110.1following the procedure described in the synthesis of compound I-109.The product was purified by preparative HPLC to afford I-110. MS (ES):m/z: 517.16 [M+H]⁺, Chiral HPLC purity: 100%, ¹H NMR (DMSO-d₆, 400 MHz):δ 10.84 (s, 1H), 9.90 (s, 1H), 8.19-8.18 (d, J=6.0 Hz, 1H), 7.96-7.95(d, J=2.4 Hz, 1H), 7.64-7.63 (d, J=2.4 Hz, 2H), 6.71-6.69 (m, 1H), 6.60(s, 1H), 5.29-5.23 (m, 1H), 4.11-4.04 (m, 2H), 3.88-3.83 (m, 2H), 3.67(s, 3H), 2.40-2.32 (m, 1H), 2.28-2.20 (m, 1H), 1.41 (s, 9H), 1.20-1.18(m, 1H), 0.77-0.75 (m, 4H).

Example 111:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-111. Compound I-111 was prepared from compound 102.2 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:505.17 [M+H]⁺, Chiral HPLC purity: 96%, ¹H NMR (DMSO-d₆, 400 MHz): 10.24(s, 1H), 9.46 (s, 1H), 8.15-8.14 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.60(s, 1H), 6.58-6.55 (m, 2H), 5.22 (s, 1H), 4.11-4.09 (m, 2H), 3.86 (bs,5H), 2.42 (s, 3H), 2.35 (bs, 1H), 2.30-2.27 (m, 1H), 2.05 (s, 3H), 1.42(s, 9H).

Example 112:(S)—N-(4-((2-((5-(tert-butyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(R)—N-(4-((2-((5-(tert-butyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-112.2. To a solution of(tetrahydrofuran-3-yl)methanol ((±)-112.1) (5.0 g, 48.96 mmol, 1.0equiv) and triethylamine (20.5 mL, 146.88 mmol, 3.0 equiv) indichloromethane (50 mL) at 0° C. was added MSCl (4.56 mL, 58.75 mmol,1.2 equiv). The reaction mixture was stirred at room temperature for 2h. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford(±)-112.2. MS (ES): m/z 181.2 [M+H]⁺.

Synthesis of compound (±)-112.4. Compound (±)-112.4 was prepared fromcompound (±)-112.2 and 19.2 following the procedure described in thesynthesis of compound 28.7. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 8-12% ethyl acetate inhexane). MS (ES): m/z 302.3 [M+H]⁺.

Synthesis of compound (±)-112.5. Compound (±)-112.5 was prepared fromcompound (±)-112.4 following the procedure described in the synthesis ofcompound 19.6. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-3% methanol in dichloromethane) to afford(±)-112.5. MS (ES): m/z 224.3 [M+H]⁺.

Synthesis of compound (±)-112. Compound (±)-112 was prepared fromcompound (±)-112.5 and 96.7 following the procedure described in thesynthesis of compound I-108. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 4.0% methanol indichloromethane). MS (ES): m/z: 505.6 [M+H]⁺.

I-112-a and I-112-b. Enantiomers of (±)-I-112 were separated on HPLC(CHIRALPAK IH (250 mm×21 mm, 5 μm); eluant: (A) 0.1% DEA in n-hexane (B)0.1% DEA in propane-2-ol:methanol (30:70); flow rate: 20 mL/min) toafford first eluting fraction (I-112-a) and second eluting fraction(I-112-b). (*Absolute stereochemistry not determined.)

I-112-a. MS (ES): m/z: 503.1 [M−H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.52(s, 1H), 9.80 (s, 1H), 8.17-8.16 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.66(s, 1H), 7.50 (s, 1H), 6.66-6.64 (m, 1H), 6.59 (bs, 1H), 4.07-4.03 (m,2H), 3.84-3.80 (m, 1H), 3.73-3.65 (m, 1H), 3.61 (s, 3H), 3.58-3.57 (m,2H), 2.89 (bs, 1H), 2.04 (s, 3H), 1.74-1.69 (m, 1H), 1.56 (bs, 1H), 1.39(s, 9H).

I-112-b. MS (ES): m/z: 505.18 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.52(s, 1H), 9.80 (s, 1H), 8.17-8.16 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.66(s, 1H), 7.50 (s, 1H), 6.66-6.64 (m, 1H), 6.59 (bs, 1H), 4.07-4.03 (m,2H), 3.84-3.80 (m, 1H), 3.73-3.65 (m, 1H), 3.61 (s, 3H), 3.58-3.57 (m,2H), 2.89 (bs, 1H), 2.04 (s, 3H), 1.74-1.69 (m, 1H), 1.56 (bs, 1H), 1.39(s, 9H).

Example 113:N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 113.2. To a solution of 113.1 (8.0 g, 124.88 mmol,1.0 equiv) and triethylamine (19.1 mL, 137.36 mmol, 1.1 equiv) indichloromethane (80 mL) at 0° C. was added triflic anhydride (22.4 mL,133.6 mmol, 1.07 equiv) slowly. The reaction mixture was stirred at 0°C. for 30 min. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford113.2, which was used in the next reaction without further purification.

Synthesis of compound 113.4. A mixture of 113.3 (1.5 g, 14.83 mmol, 1.0equiv), 113.2 (4.36 g, 22.24 mmol, 1.5 equiv) and cesium carbonate (9.63g, 29.66 mmol, 2.0 equiv) in acetonitrile (15 mL) was stirred at 80° C.for 12 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 2-3% methanol in dichloromethane) to afford113.4. ¹H NMR (CDCl₃, 400 MHz): δ 4.68-4.66 (m, 1H), 4.56-4.54 (m, 1H),3.78-3.76 (m, 1H), 2.92-2.87 (m, 2H), 2.80-2.77 (m, 1H), 2.73-2.70 (m,1H), 2.35-2.31 (m, 2H), 1.98-1.94 (m, 2H), 1.71-1.62 (m, 2H).

Synthesis of compound 113.5. To a solution of 113.4 (1.3 g, 8.83 mmol,1.0 equiv) and triethylamine (3 mL, 22.07 mmol, 2.5 equiv) indichloromethane (15 mL) at 0° C. was added MSCl (0.82 mL, 10.59 mmol,1.2 equiv). The reaction mixture was stirred at room temperature for 1h. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to afford113.5. ¹H NMR (CDCl₃, 400 MHz): δ 4.82 (bs, 1H), 4.70-4.67 (m, 1H),4.58-4.55 (m, 1H), 3.07 (s, 3H), 2.86-2.82 (m, 3H), 2.75 (bs, 1H), 2.53(bs, 2H), 2.11 (bs, 2H), 2.02-1.99 (m, 2H).

Synthesis of compound 113.7. Compound 113.7 was prepared from compound113.5 and 19.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 50-55% ethyl acetate in hexane). MS (ES):m/z 347.5 [M+H]⁺.

Synthesis of compound 113.8. Compound 113.8 was prepared from compound113.7 following the procedure described in the synthesis of compound19.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4-5% methanol in dichloromethane). MS (ES): m/z 269.4[M+H]⁺.

Synthesis of I-113. A mixture of 96.7 (0.059 g, 0.186 mmol, 1.0 equiv),113.8 (0.050 g, 0.186 mmol, 1.0 equiv) and potassium carbonate (0.077 g,0.558 mmol, 3.0 equiv) in 1,4-dioxane (2 mL) was degassed by bubblingargon through for 10 min.4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.021 g, 0.037 mmol,0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.017 g, 0.0186mmol, 0.1 equiv) were added, and degassed for 5 min. The reactionmixture was stirred at 100° C. for 4 h. It was cooled to roomtemperature, transferred into water and extracted with ethyl acetate.The combined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 6-7% methanol in dichloromethane) to affordI-113. MS (ES): m/z: 550.2 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.84 (s, 1H), 8.18-8.16 (d, J=5.6 Hz, 1H), 7.96-7.95 (d, J=2.4Hz, 1H), 7.66-7.50 (m, 2H), 6.67-6.65 (m, 1H), 6.55 (s, 1H), 4.62-4.50(m, 2H), 4.24 (bs, 1H), 3.67 (s, 3H), 3.02 (bs, 2H), 2.73-2.68 (m, 3H),2.24-2.19 (m, 4H), 2.03 (bs, 2H), 1.81 (bs, 2H), 1.39 (s, 9H).

Example 114:N-(4-((2-((5-(tert-butyl)-1-(1-(2,2-difluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 114.2. A mixture of 113.3 (1.5 g, 14.83 mmol, 1.0equiv), 2,2-difluoroethyl trifluoromethanesulfonate (114.1) (3.18 g,14.83 mmol, 1.0 equiv) and cesium carbonate (9.63 g, 29.66 mmol, 2.0equiv) in acetonitrile (30 mL) was stirred at 90° C. for 4 h. It waspoured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 60% ethyl acetate in hexane) to afford 114.2. ¹H NMR(CDCl₃, 400 MHz): δ 6.06-5.75 (m, 1H), 3.74 (bs. 1H), 2.89-2.86 (m, 2H),2.81-2.72 (m, 2H), 2.42-2.36 (m, 2H), 1.94-1.90 (m, 2H), 1.68-1.61 (m,3H).

Synthesis of compound 114.3 To a solution of 114.2 (1.1 g, 6.66 mmol,1.0 equiv) and triethylamine (1.8 mL, 13.32 mmol, 2.0 equiv) indichloromethane (15 mL) at 0° C. was added MSCl (0.62 mL, 7.99 mmol, 1.2equiv). The reaction mixture was stirred at room temperature for 12 h.It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedsodium bicarbonate followed by brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,40% ethyl acetate in hexane) to afford 114.3. ¹H NMR (CDCl₃, 400 MHz): δ6.26-5.98 (m, 1H), 4.68 (bs, 1H), 3.19 (s, 3H), 2.77-2.69 (m, 4H),2.47-2.42 (m, 2H), 1.92 (bs, 2H), 1.73-1.68 (m, 2H).

Synthesis of compound 114.5. Compound 114.5 was prepared from compound114.3 and 19.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 6-8% ethyl acetate in hexane). MS (ES): m/z365.5 [M+H]⁺.

Synthesis of compound 114.6. Compound 114.6 was prepared from compound114.5 following the procedure described in the synthesis of compound19.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4-5% methanol in dichloromethane). MS (ES): m/z 287.4[M+H]⁺.

Synthesis of I-114. Compound I-114 was prepared from compound 114.6following the procedure described in the synthesis of compound I-113.The product was purified by flash column chromatography on silica gel(CombiFlash®, 6% methanol in dichloromethane). MS (ES): m/z: 568.6[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53 (s, 1H), 9.83 (s, 1H),8.19-8.17 (m, 1H), 7.97-7.96 (d, J=2.8 Hz, 1H), 7.67-7.66 (d, J=2.4 Hz,1H), 7.64-7.63 (d, J=2.8 Hz, 1H), 6.67-6.65 (m, 1H), 6.55 (s, 1H),6.30-6.02 (m, 1H), 4.30-4.20 (m, 1H), 3.67 (s, 3H), 3.04-3.01 (m, 2H),2.84-2.75 (m, 2H), 2.34-2.33 (m, 2H), 2.24-2.19 (m, 2H), 2.04 (s, 3H),1.79-1.77 (m, 2H), 1.39 (s, 9H).

Example 115:N-(4-((2-((5-(tert-butyl)-1-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 115.1. A mixture of compound 29.7 (0.130 g, 0.434mmol, 1.0 equiv) and 20% palladium hydroxide (0.130 g) in methanol (5mL) was purged with hydrogen and stirred under 1 atm of hydrogen at rtfor 6 h. The reaction mixture was filtered through a pad of Celite® andrinsed with methanol. The filtrate was concentrated under reducedpressure to afford 115.1. MS (ES): m/z: 210.3 [M+H]⁺.

Synthesis of I-115. Compound I-115 was prepared from compound 115.1 and96.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:491.13 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.54 (s, 1H), 9.87 (s, 1H),8.18-8.17 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.66-7.63 (d, 2H), 6.66-6.59(m, 2H), 5.22-5.18 (m, 2H), 4.47 (bs, 1H), 3.68 (s, 3H), 2.73-2.68 (m,2H), 2.34 (bs, 2H), 2.04 (s, 3H), 1.37 (s, 9H).

Example 116:N-(4-((2-((5-(tert-butyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-116. Compound I-116 was prepared from compound 30.1following the procedures described in the synthesis of compound I-115.The product was purified by preparative HPLC. MS (ES): m/z: 492.3[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.53 (s, 1H), 9.87 (s, 1H),8.19-8.17 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.64-7.63 (d,J=2.4 Hz, 1H), 6.67-6.66 (m, 1H), 6.57 (s, 1H), 5.20-5.19 (d, J=5.2 Hz,1H), 4.56-4.52 (m, 1H), 4.12-4.02 (m, 1H), 3.69 (s, 3H), 3.19-3.18 (m,2H), 2.68-2.65 (m, 2H), 2.05 (s, 3H), 1.38 (s, 9H).

Example I-117:(R)—N-(4-((2-((5-(tert-butyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-117.1. Compound (±)-117.1 was prepared fromcompound 102.2 and (±)-112.5 following the procedure described in thesynthesis of compound I-113. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 4.1% methanol indichloromethane). MS (ES): m/z: 519.6 [M+H]⁺.

I-117-a and I-117-b. Enantiomers of (±)-117.1 were separated on HPLC(CHIRALPAK IH (250 mm×21 mm, 5 μm); eluant: (A) 0.1% DEA in n-hexane (B)0.1% DEA in propane-2-ol:methanol (20:80); flow rate: 18 mL/min) toafford first eluting fraction (I-117-a) and second eluting fraction(I-117-b). (*Absolute stereochemistry not determined.)

I-117-a. MS (ES): m/z: 519.15 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.71 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.60(s, 1H), 6.58 (bs, 2H), 4.08-4.01 (m, 2H), 3.85 (s, 3H), 3.73-3.58 (m,2H), 2.39 (s, 3H), 2.03 (s, 3H), 1.74-1.71 (m, 1H), 1.56 (bs, 2H), 1.38(s, 9H), 1.24 (bs, 2H).

I-117-b. MS (ES): m/z: 519.16 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.72 (s, 1H), 8.17-8.15 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.60(s, 1H), 6.58-6.56 (m, 2H), 4.12-4.04 (m, 2H), 3.85 (s, 3H), 3.73-3.58(m, 2H), 2.39 (s, 3H), 2.03 (s, 3H), 1.74-1.69 (m, 1H), 1.57 (bs, 2H),1.38 (s, 9H), 1.24 (bs, 2H).

Example 118:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypropanamide

Synthesis of compound 118.1. To a solution of 14.3 (1.3 g, 6.49 mmol,1.0 equiv) and 3-methoxypropanoic acid (0.675 g, 6.49 mmol, 1.0 equiv)in dichloromethane (50 mL) at 0° C. was added phosphorous oxychloride(1.3 mL, 1 v/w) dropwise followed by pyridine (1.3 mL, 1 v/w). Thereaction mixture was stirred at 0° C. for 3 h. It was poured over ice,neutralized with saturated aqueous sodium bicarbonate solution stirredand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2% methanol indichloromethane) to afford 118.1. MS (ES): m/z 287.3 [M+H]⁺.

Synthesis of compound 118.2. A mixture of compound 118.1 (0.820 g, 2.86mmol, 1.0 equiv) and 10% palladium on carbon (0.4 g) in methanol (20 mL)was stirred under hydrogen (1 atm) at rt for 2 h. The reaction mixturewas filtered through a pad of Celite® and rinsed with methanol. Thefiltrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 3.0%methanol in dichloromethane) to afford 118.2. MS (ES): m/z 197.2 [M+H]⁺.

Synthesis of compound 118.3. Compound 118.3 was prepared from compound118.2 and 96.3 following the procedure described in the synthesis ofcompound 96.4. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.4-2.6% methanol in dichloromethane). MS(ES): m/z 348.3 [M+H]⁺.

Synthesis of compound 118.4. Compound 118.4 was prepared from compound118.3 following the procedure described in the synthesis of compoundInt-2. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.6-3.8% methanol in dichloromethane). MS (ES): m/z318.4 [M+H]⁺.

Synthesis of compound 118.5. A solution of 118.4 (0.350 g, 1.1 mmol, 1.0equiv) and 1,1′-thiocarbonyldiimidazole (0.979 g, 5.5 mmol, 5.0 equiv)in THF (5 mL) was stirred at 70° C. for 1.5 h. It was cooled to roomtemperature and poured over ice-water. The precipitated solids werecollected by filtration and triturated with hexane to afford 118.5. MS(ES): m/z: 360.4 [M+H]⁺.

Synthesis of compound 118.6. Compound 118.6 was prepared from compound118.5 following the procedure described in the synthesis of compound102.2. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.4% methanol in dichloromethane). MS (ES): m/z 362.8[M+H]⁺.

Synthesis of I-118. Compound I-118 was prepared from compound 118.6 and24.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.8% methanol in dichloromethane). MS (ES): m/z:535.19 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54 (s, 1H), 9.91 (s, 1H),8.20-8.18 (d, J=5.6 Hz, 1H), 7.98-7.97 (d, J=2.4 Hz, 1H), 7.68-7.64 (m,2H), 6.72-6.69 (m, 1H), 6.61 (s, 1H), 5.27 (bs, 1H), 4.11-4.07 (m, 2H),3.89-3.83 (m, 2H), 3.68 (s, 3H), 3.56-3.53 (m, 2H), 3.21 (s, 3H),2.60-2.52 (m, 2H), 2.35-2.32 (m, 1H), 2.27-2.22 (m, 1H), 1.42 (s, 9H).

Example 119:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxypropanamide

Synthesis of I-119. Compound I-119 was prepared from compound 118.6 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:535.17 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54 (s, 1H), 9.91 (s, 1H),8.20-8.18 (d, J=5.6 Hz, 1H), 7.98-7.97 (d, J=2.4 Hz, 1H), 7.68-7.64 (m,2H), 6.71-6.69 (m, 1H), 6.61 (s, 1H), 5.27 (bs, 1H), 4.12-4.08 (m, 2H),3.87-3.83 (m, 2H), 3.68 (s, 3H), 3.56-3.53 (m, 2H), 3.21 (s, 3H),2.62-2.57 (m, 2H), 2.35-2.34 (m, 1H), 2.26-2.25 (m, 1H), 1.42 (s, 9H).

Example 120:(R)—N-(4-((2-((5-(tert-butyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 120.2. Compound 120.2 was prepared from compound120.1 following the procedure described in the synthesis of compound28.5. The crude product was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆, 400 MHz): δ 4.24-4.15 (m, 2H), 3.44-3.33(m, 2H), 3.25-3.23 (m, 1H), 3.20 (s, 3H), 3.04-3.01 (m, 1H), 2.55 (bs,1H), 1.96 (bs, 1H), 1.69-1.64 (m, 1H), 1.41 (s, 9H).

Synthesis of compound 120.3. Compound 120.3 was prepared from compound120.2 and 19.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 8-10% ethyl acetate in hexane) to afford120.3. MS (ES): m/z 401.5 [M+H]⁺.

Synthesis of compound 120.4. To a solution of 120.3 (0.390 g, 0.973mmol, 1.0 equiv) in dichloromethane (5 mL) was added trifluoroaceticacid (1.95 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 2 h. It was poured over ice-water, neutralized withsaturated aqueous sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford 120.4.

Synthesis of compound 120.5. To a solution of 120.4 (0.240 g, 0.798mmol, 1.0 equiv) and 1-fluoro-2-iodoethane (0.208 g, 1.20 mmol, 1.5equiv) in DMF (3 mL) was added cesium carbonate (0.518 g, 1.596 mmol,2.0 equiv). The reaction mixture was stirred at 90° C. for 2 h. It waspoured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2-2.5% methanol in dichloromethane) to afford 120.5. MS(ES): m/z 347.5 [M+H]⁺.

Synthesis of compound 120.6. A solution of 120.5 (0.180 g, 0.519 mmol,1.0 equiv) and hydroxylamine hydrochloride (1.79 g, 25.95 mmol, 50equiv) in ethanol-water (2:1) (8 mL) was stirred in a sealed tube at120° C. for 3 h. It was cooled to rt and poured over ice-water. The pHof the aqueous solution was adjusted by the addition of 2 N sodiumhydroxide to 10 and the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 8-10% methanol indichloromethane) to afford 120.6. MS (ES): m/z 269.4 [M+H]⁺.

Synthesis 1-120. Compound I-120 was prepared from compound 120.6 and96.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 5-6% methanol in dichloromethane). MS (ES): m/z: 550.6[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.25 (s, 1H), 9.57 (s, 1H),8.19-8.17 (m, 1H), 7.97 (s, 1H), 7.67-7.66 (d, J=1.6 Hz, 1H), 7.57 (s,1H), 6.68-6.66 (m, 1H), 6.46 (bs, 1H), 4.66 (bs, 1H), 4.54 (bs, 1H),4.17 (bs 2H), 3.68 (s, 3H), 2.22-2.15 (bs, 1H), 2.07 (s, 3H), 1.68-1.65(m, 2H), 1.42 (s, 9H), 1.30-1.27 (m, 6H).

Example I-121:(S)—N-(4-((2-((5-(tert-butyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-121. Compound I-121 was prepared from compound 121.1following the procedure in each step described in the synthesis ofcompound I-120. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 6-7% methanol in dichloromethane). MS (ES):m/z: 550.67 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.24 (s, 1H), 9.53 (s,1H), 8.19-8.17 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.67-7.66 (d, J=1.6 Hz,1H), 7.58 (s, 1H), 6.67-6.66 (m, 1H), 6.44 (bs, 1H), 4.72 (bs, 1H), 4.61(bs, 1H), 4.21-4.17 (m, 2H), 3.69 (s, 3H), 2.07 (bs, 4H), 1.79-1.66 (m,2H), 1.42 (s, 9H), 1.28-1.18 (m, 6H).

Example I-122:N-(4-((2-((5-(tert-butyl)-1-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 122.1. Compound 122.1 was prepared from compound102.2 and 29.7 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3% methanol in dichloromethane). MS (ES):m/z 595.7 [M+H]⁺.

Synthesis of I-122. To a solution of 122.1 (0.052 g, 0.087 mmol, 1.0equiv) in dichloromethane (3 mL) was added triflic acid (0.2 mL) at 0°C. The reaction mixture was stirred for 10 min. It was poured overice-water, neutralized with saturated aqueous sodium bicarbonatesolution and extracted with dichloromethane. The combined organic layerswere washed with brine solution, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue wasfurther purified by trituration with diethyl ether to afford I-122. MS(ES): m/z: 505.12 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.55 (s, 1H),9.76 (s, 1H), 8.18-8.16 (d, J=6 Hz, 1H), 7.89 (s, 1H), 7.62 (s, 1H),6.61-6.58 (m, 1H), 6.56 (s, 1H), 5.24-5.19 (m, 1H), 4.48 (bs, 1H), 3.88(s, 3H), 3.41-3.39 (m, 1H), 2.78-2.69 (m, 2H), 2.41 (s, 3H), 2.37-2.32(m, 2H), 2.04 (s, 3H), 1.37 (s, 9H).

Example I-123:N-(4-((2-((5-(tert-butyl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-123. Compound I-123 was prepared from compound 102.2 and30.1 following the procedures described in the synthesis of compoundI-122. The product was purified by trituration with diethyl ether. MS(ES): m/z: 505.15 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.55 (s, 1H),9.77 (s, 1H), 8.18-8.16 (d, J=6 Hz, 1H), 7.89 (s, 1H), 7.62 (s, 1H),6.60-6.58 (m, 1H), 6.53 (s, 1H), 5.22-5.21 (m, 1H), 4.54 (bs, 1H),4.05-4.03 (m, 1H), 3.88 (s, 3H), 3.41-3.39 (m, 1H), 2.69-2.64 (m, 2H),2.41 (s, 3H), 2.04 (s, 3H), 2.01 (bs, 1H), 1.37 (s, 9H).

Example I-124:(R)—N-(4-((2-((5-(tert-butyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-124. Compound I-124 was prepared from compound 102.2 and120.5 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 5-6% methanol in dichloromethane). MS (ES): m/z:564.12 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.30 (s, 1H), 9.40 (s, 1H),8.17-8.15 (d, J=5.6 Hz, 1H), 7.89 (s, 1H), 7.61-7.60 (d, J=2.0 Hz, 1H),6.61-6.59 (m, 1H), 6.40 (bs, 1H), 4.67 (bs, 1H), 4.55 (bs, 1H), 4.18 (bs2H), 3.88 (s, 3H), 2.44 (s, 3H), 2.11 (bs, 1H), 2.06 (s, 3H), 1.76 (bs,2H), 1.41 (s, 9H), 1.30-1.28 (m, 6H).

Example I-125:(S)—N-(4-((2-((5-(tert-butyl)-1-((1-(2-fluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-125. Compound I-125 was prepared from compound 102.2 and121.5 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 6-7% methanol in dichloromethane). MS (ES): m/z:563.87 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.24 (s, 1H), 9.41 (s, 1H),8.17-8.16 (d, J=5.6 Hz, 1H), 7.90 (s, 1H), 7.61-7.60 (d, J=2.0 Hz, 1H),6.60-6.59 (m, 1H), 6.46 (bs, 1H), 4.66 (bs, 1H), 4.54 (bs, 1H), 4.18 (bs2H), 3.88 (s, 3H), 2.44 (s, 3H), 2.11 (bs, 1H), 2.06 (s, 3H), 1.69 (bs,2H), 1.42 (s, 9H), 1.31-1.28 (m, 6H).

Example I-126:(R)—N-(4-((1,7-dimethyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 126.2. To a suspension of sodium hydride (6.2 g,156.18 mmol, 3.0 equiv) in THF (100 mL) was added 126.1 (10 g, 52.06mmol, 1.0 equiv) and acetonitrile (1.68 mL, 52.06 mmol, 1.0 equiv). Thereaction mixture was stirred at 50° C. for 4 h. It cooled to rt andconcentrated under reduced pressure. To the residue was added 4 Nhydrochloric acid and the mixture was extracted with diethyl ether. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 126.2. It was used in the next step without further purification.

Synthesis of compound 126.3. To a solution of 126.2 (6.0 g, 32.07 mmol,1.0 equiv) in ethanol (60 mL) was added hydrazine hydrate (98%) (3.14mL, 64.14 mmol, 2.0 equiv). The reaction mixture was refluxed for 12 h.It was cooled to rt and poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford 126.3. MS (ES): m/z 202.1 [M+H]⁺.

Synthesis of compound 126.4. To a solution of 126.3 (3.0 g, 14.92 mmol,1.0 equiv) in toluene (30 mL) was added hexane-2,5-dione (1.87 g, 16.41mmol, 1.1 equiv) followed by addition of acetic acid (0.2 mL,catalytic). The reaction mixture was refluxed for 5 h. It was pouredover water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,4-6% ethyl acetate in hexane) to afford 126.4. MS (ES): m/z 280.2[M+H]⁺.

Synthesis of compound 126.6. Compound 126.6 was prepared from compound126.4 and 23.1 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 6-8% ethyl acetate in hexane) to afford126.5, MS (ES): m/z 350.3 [M+H]⁺ and 126.6, MS (ES): m/z 350.3 [M+H]⁺.

Synthesis of compound 126.7. Compound 126.7 was prepared from compound126.6 following the procedure described in the synthesis of compound120.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3-4% methanol in dichloromethane). MS (ES): m/z 272.2[M+H]⁺.

Synthesis of I-126. Compound I-126 was prepared from compound 102.2 and126.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES): m/z: 567.7[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54 (s, 1H), 10.39 (s, 1H),8.17-8.15 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H),6.59-6.57 (m, 1H), 5.16 (bs, 1H), 4.13-4.05 (m, 2H), 3.94-3.82 (m, 5H),2.42 (s, 3H), 2.35-2.27 (m, 1H), 2.03 (s, 3H), 1.23-1.15 (m, 1H).

Example I-127:(S)—N-(4-((1,7-dimethyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-127. Compound I-127 was prepared from compound 126.4 and19.3 following the procedures described in each step in the synthesis ofcompound I-126. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES):m/z: 567.1 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.55 (s, 1H), 10.41 (s,1H), 8.17-8.16 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.39 (s,1H), 6.60-6.58 (m, 1H), 5.17 (bs, 1H), 4.14-4.06 (m, 2H), 3.95-3.83 (m,5H), 2.43 (s, 3H), 2.34-2.31 (m, 1H), 2.04 (s, 3H), 1.24 (bs, 1H).

Example 128:(R)—N-(4-((2-((5-(tert-butyl)-1-((1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-((1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-128.2. Compound (±)-128.2 was prepared fromcompound (±)-128.1 following the procedure described in the synthesis ofcompound 28.5. The crude product was used in the next step withoutfurther purification. MS (ES): m/z 218.3[M+H]⁺.

Synthesis of compound (±)-128.3. Compound (±)-128.3 was prepared fromcompound (±)-128.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 30-35% ethyl acetate in hexane). MS (ES):m/z 391.6 [M+H]⁺.

Synthesis of compound (±)-128.4. A mixture compound (±)-128.3 (0.690 g,1.77 mmol, 1.0 equiv) and 20% palladium hydroxide (0.35 g) in methanol(20 mL) was stirred under hydrogen (1 atm) at rt for 2 h. The reactionmixture was filtered through a pad of Celite® and rinsed with 10%methanol in dichloromethane. The filtrate was concentrated under reducedpressure to afford (±)-128.4. MS (ES): m/z 300.4 [M+H]⁺.

Synthesis of compound (±)-128.5. Compound (±)-128.5 was prepared fromcompound (±)-128.4 following the procedure described in the synthesis ofcompound 120.5. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 10% ethyl acetate in hexane). MS (ES): m/z383.5 [M+H]⁺.

Synthesis of compound (±)-128.6. Compound (±)-128.6 was prepared fromcompound (±)-128.5 following the procedure described in the synthesis ofcompound 120.6. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES):m/z 305.4 [M+H]⁺.

Synthesis of compound (±)-I-128. A mixture of 102.2 (0.110 g, 0.331mmol, 1.0 equiv), (±)-128.6 (0.111 g, 0.364 mmol, 1.1 equiv) and cesiumcarbonate (0.215 g, 0.662 mmol, 2.0 equiv) in 1,4-dioxane (2 mL) wasdegassed by bubbling argon through for 10 min. Under argon atmosphere4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.038 g, 0.0662 mmol,0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.0331mmol, 0.1 equiv) were added, and degassed for 5 min. The reactionmixture was stirred at 120° C. for 4 h. The reaction mixture was cooledto room temperature, transferred into water and extracted with ethylacetate. The combined organic layers were washed with brine solution,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 6-7% methanol indichloromethane) to afford (±)-128.

I-128-a and I-128-b. Enantiomers of (±)-I-128 were isolated by HPLC(CHIRALPAK IB-N (250 mm×21 mm, 5 μm), eluent: (A) 0.1% DEA in n-hexane(B) 0.1% DEA in propane-2-ol (40:60), flow rate=18 mL/min) to give thefirst eluting fraction (I-128-a) and second eluting fraction (I-128-b).(*Absolute stereochemistry not determined.)

I-128-a: MS (ES): m/z: 600.26 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53(s, 1H), 9.70 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.60(s, 1H), 6.59-6.55 (m, 2H), 4.11-3.97 (m, 2H), 3.85 (s, 3H), 3.26-3.21(m, 2H), 2.89-2.88 (m, 2H), 2.67-2.59 (m, 2H), 2.40 (s, 3H), 2.03 (s,3H), 1.97-1.95 (m, 1H), 1.58-1.55 (m, 2H), 1.38 (s, 9H).

I-128-b: MS (ES): m/z: 600.27 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.70 (s, 1H), 8.16-8.15 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.60(s, 1H), 6.59-6.55 (m, 2H), 4.10-4.00 (m, 2H), 3.85 (s, 3H), 3.26-3.21(m, 2H), 2.89-2.88 (m, 2H), 2.67-2.61 (m, 2H), 2.40 (s, 3H), 2.03 (s,3H), 1.97-1.91 (m, 1H), 1.58-1.55 (m, 2H), 1.38 (s, 9H).

Example 129:(S)—N-(4-((2-((1-((1,4-dioxan-2-yl)methyl)-5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(R)—N-(4-((2-((1-((1,4-dioxan-2-yl)methyl)-5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-129.2. To a solution of (±)-129.1 (5.0 g,48.96 mmol, 1.0 equiv) in acetonitrile (25 mL) was added sodiumbicarbonate (12.33 g, 146.88 mmol, 3.0 equiv) and iodine (37.3 g, 146.88mmol, 3.0 equiv). The reaction mixture was stirred at room temperaturefor 16 h. It was poured over crushed ice, stirred and extracted withethyl acetate. The combined organic layers were washed with aqueoussodium thiosulfate followed by brine solution, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 8-10% ethyl acetate in hexane) to afford (±)-129.2. ¹H NMR(CDCl₃, 400 MHz): δ 3.99-3.95 (m, 1H), 3.92-3.96 (m, 1H), 3.84-3.80 (m,1H), 3.70 (bs, 1H), 3.67-3.63 (m, 1H), 3.40-3.35 (m, 1H), 3.14-3.12 (m,2H).

Synthesis of compound (±)-129.3. Compound (±)-129.3 was prepared fromcompound (±)-129.2 and 19.2 following the procedure described in thesynthesis of compound 28.7. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 8% ethyl acetate in hexane).MS (ES): m/z 318.3 [M+H]⁺.

Synthesis of compound (±)-129.4. Compound (±)-129.4 was prepared fromcompound (±)-129.3 following the procedure described in the synthesis ofcompound 120.6. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES):m/z 240.3 [M+H]⁺.

Synthesis of compound 129.4-a and 129.4-b. Enantiomers of (±)-129.4 wereisolated by HPLC (CHIRALPAK IG (250 mm×21 mm, 5 μm), eluent: (A) 0.1%DEA in n-hexane (B) 0.1% DEA in propane-2-ol (50:50), flow rate=20mL/min) to get first eluting fraction (129.4-a), MS (ES): m/z: 240.3[M+H]⁺ and second eluting fraction (129.4-b), MS (ES): m/z: 240.3 [M+H]⁺(*Absolute stereochemistry not determined.)

Synthesis of I-129-a. Compound I-129-a was prepared from compound129.4-a following the procedure described in the synthesis of compoundI-128. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:535.23 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53 (s, 1H), 9.75 (s, 1H),8.16-8.15 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 6.59-6.56 (m,2H), 4.20-4.09 (m, 1H), 4.06-3.98 (m, 1H), 3.86 (s, 3H), 3.84 (bs, 1H),3.76-3.73 (m, 1H), 3.67-3.65 (m, 1H), 3.59-3.44 (m, 2H), 3.17 (bs, 2H),2.40 (s, 3H), 2.03 (s, 3H), 1.38 (s, 9H).

Synthesis of I-129-b. Compound I-129-b was prepared from compound129.4-b following the procedure described in the synthesis of compoundI-128. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:535.53 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53 (s, 1H), 9.75 (s, 1H),8.16-8.15 (d, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 6.59-6.56 (m,2H), 4.20-4.09 (m, 1H), 4.06-3.98 (m, 1H), 3.86 (s, 3H), 3.84 (bs, 1H),3.76-3.73 (m, 1H), 3.67-3.65 (m, 1H), 3.59-3.44 (m, 2H), 3.17 (bs, 2H),2.40 (s, 3H), 2.03 (s, 3H), 1.38 (s, 9H).

Example 130:N-(4-((2-((5-(tert-butyl)-1-(2-fluoroethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 130.1. Compound 130.1 was prepared from compound19.2 and 1-fluoro-2-iodoethane following the procedure described in thesynthesis of compound 28.7. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 8-10% ethyl acetate inhexane). MS (ES): m/z 264.3 [M+H]⁺.

Synthesis of compound 130.2. Compound 130.2 was prepared from compound130.1 following the procedure described in the synthesis of compound120.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES): m/z 186.3[M+H]⁺.

Synthesis of I-130. Compound I-130 was prepared from compound 130.2 and102.2 following the procedure described in the synthesis of compoundI-128. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4-5% methanol in dichloromethane). MS (ES): m/z:467.24 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.54 (s, 1H), 9.93 (s, 1H),8.18-8.16 (d, J=6.0 Hz, 1H), 7.97-7.96 (d, J=2.4 Hz, 1H), 7.66-7.63 (m,2H), 6.66-6.63 (m, 2H), 4.95 (bs, 1H), 4.83 (bs, 1H), 4.48-4.43 (m, 2H),3.66 (s, 3H), 2.03 (s, 3H), 1.39 (s, 9H).

Example 131:N-(4-((2-((5-(tert-butyl)-1-(cyanomethyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 131.1. To a solution of 19.2 (5.0 g, 23.01 mmol,1.0 equiv) in DMF (25 mL) was added sodium hydride (3.6 g, 92.04 mmol,4.0 equiv) in small portions at 0° C. The reaction mixture was stirredat 0° C. for 2 h followed by the addition of bromoacetonitrile (13.7 g,115.08 mmol, 5.0 equiv) dropwise. The reaction mixture was stirred atroom temperature for 16 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 6-8% ethyl acetate inhexane) to afford 131.1. MS (ES): m/z 257.3 [M+H]⁺.

Synthesis of compound 131.2. To a suspension of 131.1 (0.465 g, 1.82mmol, 1.0 equiv) in water (20 mL) was added trifluoroacetic acid (10mL). The reaction mixture was stirred at 120° C. for 10 min. It waspoured over ice-water, followed by addition of saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The combinedorganic layers were washed with brine solution, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford crude. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 70% ethyl acetate in hexane) to afford 131.2.MS (ES): m/z 179.2 [M+H]⁺.

Synthesis of I-131. Compound I-131 was prepared from compound 131.2 and102.2 following the procedure described in the synthesis of compoundI-128. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:474.28 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.54 (s, 1H), 9.97 (s, 1H),8.16-8.15 (d, J=5.6 Hz, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 6.69 (s, 1H),6.59-6.58 (m, 1H), 5.46 (s, 2H), 3.94 (s, 3H), 2.41 (s, 3H), 2.03 (s,3H), 1.40 (s, 9H).

Example 132:N-(4-((2-((5-(tert-butyl)-1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-132. Compound I-132 was prepared from compound 19.2 and2,2-difluoroethyl trifluoromethanesulfonate following the proceduredescribed in each step in the synthesis of compound I-130. The productwas purified by flash column chromatography on silica gel (CombiFlash®,4.5% methanol in dichloromethane). MS (ES): m/z: 485.37 [M+H]⁺, ¹H NMR(DMSO-d₆, 400 MHz): 10.54 (s, 1H), 10.01 (s, 1H), 8.19-8.17 (d, J=5.6Hz, 1H), 7.98 (s, 1H), 7.66 (s, 1H), 7.08 (bs, 1H), 6.83 (bs, 1H),6.70-6.66 (m, 1H), 6.46 (bs, 1H), 4.65-4.59 (m, 2H), 3.68 (s, 3H), 2.04(s, 3H), 1.40 (s, 9H).

Example 133:(R)—N-(4-((1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 133.1. To a solution of 14.13 (0.500 g, 1.67 mmol,1.0 equiv) in THF (10 mL) was added 1,1′-thiocarbonyldiimidazole (1.48g, 8.35 mmol, 5.0 equiv). The reaction mixture was stirred at 80° C. for1 h. It was cooled to room temperature and poured over ice-water.Precipitated solid was collected by filtration and dried under vacuum toafford 133.1. MS (ES): m/z: 342.4 [M+H]⁺.

Synthesis of compound 133.2. Compound 133.2 was prepared from compound133.1 following the procedure described in the synthesis of compound102.2. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.4% methanol in dichloromethane. MS (ES): m/z 344.7[M+H]⁺.

Synthesis of I-133. Compound I-133 was prepared from compound 133.2 and126.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 1.8-2.0% methanol in dichloromethane). MS (ES): m/z:579.7 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H), 10.52 (s, 1H),8.19-8.18 (d, J=5.6 Hz, 1H), 8.01-8.00 (d, J=2.4 Hz, 1H), 7.72-7.71 (d,J=2.4 Hz, 1H), 7.63-7.61 (d, J=2.0 Hz, 1H), 7.41 (s, 1H), 6.70-6.68 (m,1H), 5.16 (bs, 1H), 4.13-4.05 (m, 2H), 3.94-3.91 (m, 1H), 3.87-3.82 (m,1H), 3.71 (s, 3H), 2.43-2.39 (m, 1H), 2.33-2.30 (m, 1H), 1.97-1.94 (m,1H), 0.76-0.74 (m, 4H).

Example 134:(S)—N-(4-((1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-134. Compound I-134 was prepared from compound 133.2 and127.3 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.0% methanol in dichloromethane). MS (ES): m/z: 579.2[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.85 (s, 1H), 10.53 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.02-8.01 (d, J=2.4 Hz, 1H), 7.73-7.72 (d,J=2.4 Hz, 1H), 7.64-7.63 (d, J=2.0 Hz, 1H), 7.42 (s, 1H), 6.71-6.69 (m,1H), 5.17 (bs, 1H), 4.14-4.06 (m, 2H), 3.95-3.92 (m, 1H), 3.87-3.82 (m,1H), 3.72 (s, 3H), 2.43-2.42 (m, 1H), 2.34-2.29 (m, 1H), 1.98-1.95 (m,1H), 0.77-0.75 (m, 4H).

Example 135:(S)—N-(4-((2-((1-((1,4-dioxan-2-yl)methyl)-5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamideand(R)—N-(4-((2-((1-((1,4-dioxan-2-yl)methyl)-5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-135-a. Compound I-135-a was prepared from compound 133.2and 129.4-a following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES):m/z: 547.8 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H), 9.90 (s,1H), 8.20-8.19 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.64 (s, 2H), 6.71-6.69(m, 1H), 6.61 (s, 1H), 4.22-4.17 (m, 1H), 4.10-3.96 (m, 2H), 3.87-3.84(m, 1H), 3.77-3.74 (m, 1H), 3.67 (s, 4H), 3.51-3.38 (m, 3H), 2.00-1.95(m, 1H), 1.39 (s, 9H), 0.77-0.75 (m, 4H).

Synthesis of I-135-b. Compound I-135-b was prepared from compound 133.2and 129.4-b following the procedure described in the synthesis ofcompound I-108. The product was was purified by flash columnchromatography on silica gel (CombiFlash®, 3.6% methanol indichloromethane). MS (ES): m/z: 547.8 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz):δ 10.85 (s, 1H), 9.90 (s, 1H), 8.20-8.19 (d, J=5.6 Hz, 1H), 7.97-7.96(d, J=2.4 Hz, 1H), 7.64 (s, 2H), 6.71-6.69 (m, 1H), 6.61 (s, 1H),4.22-4.17 (m, 1H), 4.11-4.00 (m, 2H), 3.88-3.83 (m, 1H), 3.77-3.74 (m,1H), 3.67 (s, 4H), 3.51-3.38 (m, 3H), 1.98-1.95 (m, 1H), 1.40 (s, 9H),0.77-0.75 (m, 4H).

Example 136:N-(4-((2-((5-(tert-butyl)-1-(2-cyanoethyl)-1H-pyrazol-3-yl)amino)-1,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 136.1. To a solution of 19.2 (15 g, 69.02 mmol,1.0 equiv) in acetonitrile (150 mL) was added acrylonitrile (5.4 mL,82.8 mmol, 1.2 equiv). The reaction mixture was stirred at roomtemperature for 16 h. It was poured over ice-water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 12-15% ethyl acetatein hexane) to afford 136.1. MS (ES): m/z 271.3 [M+H]⁺.

Synthesis of compound 136.2. Compound 136.2 was prepared from compound136.1 following the procedure described in the synthesis of compound131.2. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4% methanol in dichloromethane). MS (ES): m/z 193.2[M+H]⁺.

Synthesis of compound 136.3. To a solution of 102.1 (0.400 g, 0.261mmol, 1.0 equiv) in acetic acid (10 mL) was added aqueous hydrobromicacid (0.029 g, 0.365 mmol, 1.4 equiv) at 0° C. followed by bromine(0.150 g, 0.939 mmol, 3.6 equiv). The reaction mixture was stirred for10 min. It was poured into a saturated aqueous sodium bicarbonatesolution, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 1.8%methanol in dichloromethane) to afford 136.3. MS (ES): m/z 377.2 [M+H]⁺.

Synthesis of I-136. A mixture of 136.3 (0.100 g, 0.265 mmol, 1.0 equiv),136.2 (0.051 g, 0.265 mmol, 1.0 equiv) and tripotassium phosphate (0.393g, 1.85 mmol, 7.0 equiv) in DMF (4 mL) was degassed by bubbling argonthrough for 10 min. Under argon atmosphere[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.084 g, 0.106 mmol, 0.4 equiv) wasadded, and degassed for 5 min. The reaction mixture was stirred at roomtemperature for 16 h. It was poured over water and extracted with ethylacetate. The combined organic layers were washed with brine solution,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 3.2% methanol indichloromethane) to afford I-136. MS (ES): m/z: 488.21 [M+H]⁺, ¹H NMR(DMSO-d₆, 400 MHz): 10.53 (s, 1H), 9.81 (s, 1H), 8.16-8.15 (d, J=5.6 Hz,1H), 7.89 (s, 1H), 7.60 (s, 1H), 6.60-6.57 (m, 2H), 4.41-4.38 (m, 2H),3.86 (s, 3H), 3.13-3.10 (m, 2H), 2.40 (s, 3H), 2.03 (s, 3H), 1.40 (s,9H).

Example 137:N-(4-((2-((5-(tert-butyl)-1-(2-cyanoethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-137. Compound I-137 was prepared from compound 136.2 and133.2 following the procedure described in the synthesis of compoundI-136. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.0% methanol in dichloromethane). MS (ES): m/z:500.20 [M+H]⁺, LCMS purity: 100%, HPLC purity: 99.24%, ¹H NMR (DMSO-d₆,400 MHz): 10.83 (s, 1H), 9.94 (s, 1H), 8.19-8.17 (d, J=5.6 Hz, 1H), 7.96(s, 1H), 7.64-7.63 (d, J=2.8 Hz, 2H), 6.70-6.68 (m, 1H), 6.64 (bs, 1H),4.41-4.38 (m, 2H), 3.66 (s, 3H), 3.13-3.09 (m, 2H), 1.97-1.94 (m, 1H),1.40 (s, 9H), 0.74 (bs, 4H).

Example 138:(R)—N-(4-((2-((5-(tert-butyl)-4-fluoro-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 138.2. To a solution of 138.1 (2.5 g, 42.34 mmol,1.0 equiv) in THF (25 mL) was added pivaloyl chloride (5.11 g, 42.34mmol, 1.0 equiv) and the reaction mixture was cooled to −78° C. To thisadded lithium bis(trimethylsilyl)amide (1 M in THF) (84.6 mL, 84.68mmol, 2.0 equiv). The reaction mixture was allowed to warm to roomtemperature followed by addition of 1 N hydrochloric acid until pH=2.The reaction mixture was extracted with hexane. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford 138.2. Thecrude product was used in the next step without further purification.

Synthesis of compound 138.3. To a solution of 138.2 (3.5 g, 24.45 mmol,1.0 equiv) in ethanol (35 mL) was added hydrazine hydrate (98%) (2.9 mL,58.68 mmol, 2.4 equiv). The reaction mixture was refluxed for 4 h. Itwas poured over ice-water, stirred and extracted with dichloromethane.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford 138.3. MS (ES): m/z 158.1 [M+H]⁺.

Synthesis of compound 138.4. Compound 138.4 was prepared from compound138.3 following the procedure described in the synthesis of compound126.4. The product was purified by flash column chromatography on silicagel (CombiFlash®, 5-7% ethyl acetate in hexane). MS (ES): m/z 236.3[M+H]⁺.

Synthesis of compound 138.6. Compound 138.6 was prepared from compound138.4 and 23.1 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 8-10% ethyl acetate in hexane). 138.5: MS(ES): m/z 306.4 [M+H]⁺ and 138.6: MS (ES): m/z 306.4 [M+H]⁺.

Synthesis of compound 138.7. Compound 138.7 was prepared from compound138.6 following the procedure described in the synthesis of compound120.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 40% ethyl acetate in hexane). MS (ES): m/z 228.3[M+H]⁺.

Synthesis of I-138. Compound I-138 was prepared from compound 138.7 and96.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES): m/z:509.44 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53 (s, 1H), 9.39 (s, 1H),8.18-8.16 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H),6.68-6.64 (m, 1H), 5.27 (bs, 1H), 4.13-4.01 (m, 2H), 3.88-3.66 (m, 2H),3.43 (s, 3H), 2.41-2.34 (m, 1H), 2.22-2.21 (m, 1H), 2.04 (s, 3H), 1.44(s, 9H).

Example 139:(S)—N-(4-((2-((5-(tert-butyl)-4-fluoro-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-139. Compound I-139 was prepared from compound 138.4 and19.3 following the procedure described in each step in the synthesis ofcompound I-138. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-3% methanol in dichloromethane). MS (ES):m/z: 509.44 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53 (s, 1H), 9.39 (s,1H), 8.17-8.15 (d, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 7.69 (s,1H), 6.69-6.64 (m, 1H), 5.26 (bs, 1H), 4.12-4.00 (m, 2H), 3.89-3.77 (m,2H), 3.65 (s, 3H), 2.41-2.34 (m, 1H), 2.21-2.20 (m, 1H), 2.03 (s, 3H),1.46 (s, 9H).

Example 140:N-(4-((2-((5-(tert-butyl)-1-(cyanomethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-140. Compound I-140 was prepared from compound 130.2 and133.2 following the procedure described in the synthesis of compoundI-136. The product was purified by preparative HPLC. MS (ES): m/z: 485.9[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.83 (s, 1H), 10.08 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 7.99 (s, 1H), 7.67-7.64 (d, J=9.6 Hz, 2H),6.74 (s, 1H), 6.71-6.70 (d, J=3.6 Hz, 1H), 5.48 (bs, 2H), 3.69 (s, 3H),2.00-1.92 (m, 1H), 1.41 (s, 9H), 0.75 (bs, 4H).

Example 141:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 141.1. To a solution of 98.1 (10 g, 76.87 mmol,1.0 equiv) in THF (200 mL), was added n-butyl lithium (2.5M in hexane)(61.4 mL, 153.7 mmol, 2.0 equiv) at −78° C. and stirred for 40 min.Hexachloroethane (36.3 g, 153.7 mmol, 2.0 equiv) was added and thereaction mixture was stirred at −78° C. for 40 min. A saturated aqueousammonium chloride solution was added carefully to quench the reaction.The mixture was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue by flashcolumn chromatography on silica gel (CombiFlash®, 12% ethyl acetate inhexane) to afford 141.1. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.98-7.94 (m, 1H),6.48 (bs, 2H).

Synthesis of compound 141.2. Concentrated sulfuric acid (3 mL) was addeddropwise to potassium persulfate (2.05 g, 7.6 mmol, 2.5 equiv) at roomtemperature and stirred for 15 min. To the mixture was added 141.1 (0.5g, 3.04 mmol, 1.0 equiv) in small portions while maintaining temperaturein the range of 30−40° C. After the addition the reaction mixture wasstirred at room temperature for 3-4 h. It was poured over crushed ice,stirred and basified with saturated sodium bicarbonate and extractedwith ethyl acetate. The combined organic layers were washed with brinesolution, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2-3% ethyl acetate in hexane)to afford 141.2. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.78 (s, 1H).

Synthesis of compound 141.3. To a solution of 141.2 (0.970 g, 4.99 mmol,1.0 equiv) in acetonitrile (10 mL) was added aqueous methylaminesolution (40%) (0.8 mL, 9.98 mmol, 2.0 equiv) dropwise at 0° C. Thereaction mixture was allowed to warm to at room temperature and stirredfor 20 min. It was poured over ice-water and extracted with ethylacetate. The combined organic layers were washed with brine solution,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane)to afford 141.3. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.98 (s, 1H), 7.05 (bs,1H), 2.79 (d, 3H).

Synthesis of compound 141.4. A mixture of 141.3 (0.930 g, 4.52 mmol, 1.0equiv) in DMF (10 mL), Int-1 (0.895 g, 5.88 mmol, 1.3 equiv) and sodiumcarbonate (0.958 g, 9.04 mmol, 2.0 equiv) was stirred at 50° C. for 6 h.The reaction mixture was cooled to room temperature, poured overice-water. The precipitated solids were collected by filtration, rinsedwith water and dried under vacuum to afford 141.4. MS (ES): m/z 338.7[M+H]⁺.

Synthesis of compound 141.5. To a solution of compound 141.4 (0.850 g,2.52 mmol, 1.0 equiv) in ethanol-water (8:2, 10 mL) was added ironpowder (0.705 g, 12.6 mmol, 5.0 equiv) followed by ammonium chloride(0.673 g, 12.6 mmol, 5.0 equiv). The reaction mixture was stirred at 80°C. for 2 h. It was filtered through a pad of Celite® and rinsed withethanol. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.4% methanol in dichloromethane) to afford 141.5. MS(ES): m/z 308.5 [M+H]⁺.

Synthesis of I-141. To a solution of 141.5 (0.100 g, 0.324 mmol, 1.0equiv) in THF (5 mL) was added sodium hydride (0.065 g, 1.62 mmol, 5.0equiv) at 0° C. and stirred for 30 min. To the mixture was addedsolution of 24.2 (0.163 g, 0.649 mmol, 2.0 equiv) in THF (2 mL). Thereaction mixture was stirred at 60° C. for 3 h. It was cooled to roomtemperature, poured over ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine solution, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was further purified by preparative HPLC to affordI-141. MS (ES): m/z: 525.45 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.57(s, 1H), 10.03 (s, 1H), 8.18-8.17 (d, J=5.6 Hz, 1H), 8.08 (s, 1H), 7.64(s, 1H), 6.65-6.63 (m, 1H), 6.56 (s, 1H), 5.26 (m, 1H), 4.11-4.06 (m,2H), 3.93 (s, 3H), 3.88-3.82 (m, 2H), 2.26-2.23 (m, 2H), 2.04 (s, 3H),1.40 (s, 9H).

Example 142:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 142.1. To a solution of 141.4 (0.150 g, 0.487mmol, 1.0 equiv) in THF (2 mL) was added 1,1′-thiocarbonyldiimidazole(0.433 g, 2.43 mmol, 5.0 equiv). The reaction mixture was stirred at 80°C. for 1 h. The reaction mixture was cooled to room temperature andpoured over ice-water. Precipitated solid was filtered out andtriturated with hexane to afford 142.1. MS (ES): m/z: 350.7 [M+H]⁺.

Synthesis of compound 142.2. Compound 142.2 was prepared from compound142.1 following the procedure described in the synthesis of compound136.3. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.5% methanol in dichloromethane). MS (ES): m/z 397.6[M+H]⁺.

Synthesis of I-142. Compound I-142 was prepared from compound 142.2 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.8% methanol in dichloromethane). MS (ES): m/z:525.88 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.57 (s, 1H), 10.03 (s,1H), 8.18-8.17 (d, J=5.6 Hz, 1H), 8.08 (s, 1H), 7.64 (s, 1H), 6.65-6.63(m, 1H), 6.56 (s, 1H), 5.26 (m, 1H), 4.11-4.06 (m, 2H), 3.93 (s, 3H),3.88-3.82 (m, 2H), 2.26-2.23 (m, 2H), 2.04 (s, 3H), 1.40 (s, 9H).

Example 143:(R)—N-(4-((2-((5-(tert-butyl)-1-(((4-methylmorpholin-2-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 143.2. Compound 143.2 was prepared from compound143.1 following the procedure described in the synthesis of compound28.5. The crude product was used without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 4.25-4.24 (d, 2H), 3.94-3.91 (m, 3H), 3.72-3.69 (m,1H), 3.59-3.50 (m, 1H), 3.08 (s, 3H), 2.97 (bs, 1H), 2.78 (bs, 1H), 1.48(s, 9H).

Synthesis of compound 143.3. Compound 143.3 was prepared from compound143.2 following the procedure described in the synthesis of compound28.7. The product was purified by flash column chromatography on silicagel (CombiFlash®, 10-12% ethyl acetate in hexane) to afford 143.3. MS(ES): m/z 403.5 [M+H]⁺.

Synthesis of compound 143.4. To a solution of 143.3 (1.67 g, 4.15 mmol,1.0 equiv) in dichloromethane (20 mL) was added hydrogen chloridesolution (4.0 M in dioxane) (11.7 mL) at 0° C. The reaction mixture wasstirred at room temperature for 2 h. It was transferred into ice-water,neutralized with saturated sodium bicarbonate solution and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated underreduced pressure to afford 143.4. It was used without furtherpurification.

Synthesis of compound 143.5. To a solution of 143.4 (1.1 g, 3.48 mmol,1.0 equiv) in 1,2-dichloroethane-methanol (2:1, 10 mL) was addedformaldehyde solution (37% in water) (1.4 mL, 17.4 mmol, 5.0 equiv). Thereaction mixture was stirred at room temperature for 30 min. To mixturewas added acetic acid (0.49 mL, 8.7 mmol, 2.5 equiv) followed by sodiumcyanoborohydride (1.1 g, 17.4 mmol, 5.0 equiv). After completion ofreaction, it was transferred into ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3.0-3.5% methanol in dichloromethane) to afford 143.5. MS(ES): m/z 331.5 [M+H]⁺.

Synthesis of compound 143.6. Compound 143.6 was prepared from compound143.5 following the procedure described in the synthesis of compound120.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 7-8% methanol in dichloromethane) to afford 143.6. MS(ES): m/z 253.3 [M+H]⁺.

Synthesis of I-143. Compound I-143 was prepared from compound 143.6 and96.7 following the procedure described in the synthesis of compoundI-136. The product was purified by preparative HPLC. MS (ES): m/z: 534.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.53 (s, 1H), 9.87 (s, 1H), 8.31 (s,1H), 8.18-8.16 (d, J=6.0 Hz, 1H), 7.96 (s, 1H), 7.66-7.63 (m, 2H),6.66-6.64 (m, 1H), 6.60 (s, 1H), 4.23-4.17 (m, 1H), 4.05-3.99 (m, 3H),3.80-3.77 (m, 2H), 3.53-3.45 (m, 1H), 2.80-2.77 (m, 2H), 2.60-2.57 (m,2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.38 (s, 9H).

Example I-144:(S)—N-(4-((2-((5-(tert-butyl)-1-(((4-methylmorpholin-2-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-144. Compound I-144 was prepared from compound 144.1following the procedure described in each step in the synthesis ofcompound I-143. The product was purified by preparative HPLC. MS(ES):m/z: 534.9 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.53 (s, 1H), 9.89 (s,1H), 8.27 (s, 1H), 8.19-8.17 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.67-7.64(m, 2H), 6.67-6.65 (m, 1H), 6.61 (s, 1H), 4.22-4.18 (m, 1H), 4.08-4.04(m, 3H), 3.81-3.78 (m, 2H), 3.51-3.45 (m, 1H), 2.81-2.78 (m, 2H),2.60-2.57 (m, 2H), 2.20 (s, 3H), 2.04 (s, 3H), 1.38 (s, 9H).

Example 145:(R)—N-(4-((7-chloro-1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-145. Compound I-145 was prepared from compound 142.2 and127.3 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.0% methanol in dichloromethane). MS (ES): m/z: 587.8[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.65 (s, 1H), 10.59 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H),6.67-6.65 (m, 1H), 5.18 (bs, 1H), 4.15-4.07 (m, 2H), 3.98-3.93 (m, 4H),3.89-3.83 (m, 1H), 2.46-2.41 (m, 1H), 2.34-2.31 (m, 1H), 2.05 (s, 3H).

Example 146:(S)—N-(4-((7-chloro-1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-146. Compound I-146 was prepared from compound 142.2 and126.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.0% methanol in dichloromethane). MS (ES): m/z: 587.8[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.65 (s, 1H), 10.59 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H),6.67-6.65 (m, 1H), 5.18 (bs, 1H), 4.15-4.07 (m, 2H), 3.98-3.93 (m, 4H),3.89-3.83 (m, 1H), 2.46-2.41 (m, 1H), 2.34-2.31 (m, 1H), 2.05 (s, 3H).

Example I-147:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 147.1. To a solution of 98.2 (15 g, 87.14 mmol,1.0 equiv) and N-formylmorpholine (26.1 mL, 261.4 mmol, 3.0 equiv) inTHF (150 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in THF)(200 mL, 200.4 mmol, 2.3 equiv) at −20° C. dropwise. After the addition,the reaction mixture was stirred at same temperature for 2 h. It waspoured into a cold aqueous solution of citric acid monohydrate (60.4 g)and sodium chloride (15 g) and the mixture was stirred at 0° C. for 15min. The organic layer was separated, washed with 50% dipotassiumhydrogen phosphate aqueous solution followed by brine. It was dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 70% ethyl acetate in hexane) to afford 147.1. ¹H NMR(DMSO-d₆, 400 MHz): δ 10.46 (s, 1H), 10.22 (s, 1H), 8.53 (s, 1H), 2.09(s, 3H).

Synthesis of compound 147.2. To a solution of 147.1 (1.0 g, 5.0 mmol,1.0 equiv) in dichloromethane (10 mL), was added diethylaminosulfurtrifluoride (0.65 mL, 5.0 mmol, 1.0 equiv) dropwise at 0° C. Thereaction mixture was stirred at same temperature for 30 min. It wastransferred into saturated sodium bicarbonate solution and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 35-40% ethyl acetate in hexane) to afford147.2. ¹H NMR (CDCl₃, 400 MHz): δ 8.27 (s, 1H), 7.63 (s, 1H), 7.12-6.86(m, 1H), 2.38 (s, 3H).

Synthesis of compound 147.3. To a solution of 147.2 (1.8 g, 8.10 mmol,1.0 equiv) in methanol (10 mL), was added concentrated hydrochloric acid(3 mL). The reaction mixture was refluxed for 1 h. It was concentratedunder reduced pressure. To the residue was added ice-water and it wasneutralized by saturated sodium bicarbonate solution and extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(CombiFlash®, 15-20% ethyl acetate in hexane) to afford 147.3. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.99 (s, 1H), 7.44-7.18 (m, 1H), 6.54 (s, 2H).

Synthesis of compound 147.4. Compound 147.4 was prepared from compound147.3 following the procedure described in the synthesis of compound141.2. The product was purified by flash column chromatography on silicagel (CombiFlash®, 8-10% ethyl acetate in hexane) to afford 147.4. ¹H NMR(CDCl₃, 400 MHz): δ 8.69 (s, 1H), 7.28-6.91 (m, 1H).

Synthesis of compound 147.5. To a solution of 147.4 (0.155 g, 0.737mmol, 1.0 equiv) in acetonitrile (3 mL) was added aqueous methylaminesolution (40%) (0.06 mL, 0.737 mmol, 1.0 equiv) dropwise at 0° C. Thereaction mixture was stirred at room temperature for 2-3 h. It wastransferred into ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine solution, dried oversodium sulfate, filtered and concentrated under reduced pressure toafford 147.5. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.96 (s, 1H), 7.54-7.41 (m,1H), 2.86 (d, 3H).

Synthesis of compound 147.6. A mixture of 147.5 (0.120 g, 0.542 mmol,1.0 equiv) in DMF (2 mL), Int-1 (0.091 g, 0.596 mmol, 1.1 equiv) andsodium carbonate (0.110 g, 1.082 mmol, 2.0 equiv) was stirred at 70° C.for 1 h. It was cooled to room temperature, transferred into ice-waterand extracted with ethyl acetate. The combined organic layers werewashed with brine solution, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 25-30% ethyl acetatein hexane) to afford 147.6. MS(ES): m/z 354.3 [M+H]⁺.

Synthesis of compound 147.7. Compound 147.7 was prepared from compound147.6 following the procedure described in the synthesis of compound141.5. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.2% methanol in dichloromethane) to afford 147.7.MS(ES): m/z 324.3 [M+H]⁺.

Synthesis of compound 147.8. To a solution of 147.7 (0.060 g, 0.185mmol, 1.0 equiv) in THF (2 mL) was added 1,1′-thiocarbonyldiimidazole(0.164 g, 0.925 mmol, 5.0 equiv). The reaction mixture was stirred at80° C. for 1 h. It was cooled to room temperature and poured intoice-water. The precipitates formed were collected by filtration andtriturated with hexane to obtain 147.8. MS(ES): m/z: 366.3 [M+H]⁺.

Synthesis of compound 147.9. To a solution of 147.8 (0.040 g, 0.109mmol, 1.0 equiv) in acetic acid (2 mL) was added aqueous hydrobromicacid (0.013 g, 0.163 mmol, 1.5 equiv) at 0° C. followed by bromine(0.078 g, 0.436 mmol, 4.0 equiv). The reaction mixture was stirred for10 min. It was poured into a saturated sodium bicarbonate solution,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was further purified byflash column chromatography on silica gel (CombiFlash®, 2.3% methanol indichloromethane) to afford 147.9. MS (ES): m/z 413.2 [M+H]⁺.

Synthesis of I-147. Compound I-147 was prepared from compound 147.9 and24.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS(ES): m/z: 541.56[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.60 (s, 1H), 10.13 (s, 1H),8.21-8.20 (d, J=5.6 Hz, 1H), 8.08 (s, 1H), 7.68 (s, 1H), 7.49-7.23 (m,1H), 6.67-6.65 (m, 1H), 6.58 (s, 1H), 5.28 (s, 1H), 4.12-4.09 (m, 2H),3.89-3.80 (m, 5H), 2.39-2.35 (m, 1H), 2.27-2.23 (m, 1H), 2.05 (s, 3H),1.42 (s, 9H).

Example 148:(R)—N-(4-((2-((5-(tert-butyl)-1-((3,3-difluoro-1-methylpiperidin-4-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-((3,3-difluoro-1-methylpiperidin-4-yl)methyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 148.1. To a solution of methyltriphenylphosphoniumbromide (47.54 g, 133.18 mmol, 1.5 equiv) in THF (100 mL) was addedsolution of potassium tert-butoxide (1 M in THF) (133.2 mL, 133.18 mmol,1.5 equiv) at 0° C. The solution was allowed to warm to room temperatureand stirred for 30 min. It was cooled to 0° C. and was added to asolution of 1-benzyl-3,3-difluoropiperidin-4-one (20 g, 88.79 mmol, 1.0equiv) in THF (100 mL) stirring at room temperature for 16 h. It waspoured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4-6% ethyl acetate in hexane) to afford the 148.1. MS(ES): m/z 224.3 [M+H]⁺.

Synthesis of compound 148.2. To a solution of 148.1 (8.0 g, 35.83 mmol,1.0 equiv) in THF (100 mL) was added borane-THF (1 M in THF) (72 mL,71.66 mmol, 2.0 equiv) and stirred at 70° C. for 2 h. The reactionmixture was cooled to 0° C. and was added 2 N sodium hydroxide solution(100 mL) followed by 30% hydrogen peroxide (100 mL). It was stirred atroom temperature for 15 min and 40° C. for 16 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,25-30% ethyl acetate in hexane) to afford 148.2. MS (ES): m/z 242.3[M+H]⁺.

Synthesis of compound 148.3. Compound 148.3 was prepared from compound148.2 following the procedure described in the synthesis of compound28.5. The crude product was used in the next step without furtherpurification. MS (ES): m/z 320.4 [M+H]⁺.

Synthesis of compound 148.4. Compound 148.4 was prepared from compound148.3 and 19.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2-2.5% ethyl acetate in hexane) to afford148.4. MS (ES): m/z 441.5 [M+H]⁺.

Synthesis of compound 148.5. A mixture of compound 148.4 (0.600 g, 1.36mmol, 1.0 equiv) and 20% palladium hydroxide (0.600 g) in methanol (20mL) was stirred under hydrogen (1 atm) for 3-4 h. The reaction mixturewas filtered through a pad of Celite® and washed with 10% methanol indichloromethane. The filtrate was concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(CombiFlash®, 1.6-1.8% methanol in dichloromethane) to afford 148.5. MS(ES): m/z 351.4 [M+H]⁺.

Synthesis of compound 148.6. To a solution of 148.5 (0.330 g, 0.941mmol, 1.0 equiv) in methanol (10 mL) and formaldehyde (37% in water)(0.38 mL, 4.70 mmol, 5.0 equiv) was stirred at room temperature for 30min. To the solution was added acetic acid (0.13 mL, 2.35 mmol, 2.5equiv) followed by sodium cyanoborohydride (0.296 g, 4.70 mmol, 5.0equiv) in portions. The reaction mixture stirred at room temperature for10 min. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford 148.6.MS (ES): m/z 365.5 [M+H]⁺.

Synthesis of compound 148.7. Compound 148.7 was prepared from compound148.6 following the procedure described in the synthesis of compound28.8.

Synthesis of compound 148.8. To a solution of 96.5 (3.5 g, 12.81 mmol,1.0 equiv) in THF (35 mL) was added 1,1′-thiocarbonyldiimidazole (11.4g, 64.05 mmol, 5.0 equiv). The reaction mixture was stirred at 80° C.for 1 h. It was cooled to room temperature and poured into ice-water.Precipitated solids were collected by filtration and dried under reducedpressure to obtain 148.7. MS(ES): m/z: 316.3 [M+H]⁺.

Synthesis of compound 148.9. To a solution of 148.8 (0.510 g, 1.62 mmol,1.0 equiv) in acetic acid (10 mL) was added aqueous hydrobromic acid(0.524 g, 3.24 mmol, 2.0 equiv) at 0° C. followed by bromine (1.036 g,6.48 mmol, 4.0 equiv). It was stirred for 10 min and poured into asaturated aqueous sodium bicarbonate solution, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5-3.0% methanol indichloromethane) to afford 148.8. MS (ES): m/z 363.2 [M+H]⁺.

Synthesis of (±)-I-148. Compound I-148 was prepared from compound 148.7and 148.9 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.5% methanol in dichloromethane) to afford theracemic product.

Synthesis of compound I-148-a and I-148-b. The two enantiomers wereseparated by chiral SFC (CHIRALPAK IC (250 mm×21 mm, 5 μm), eluent: (A)Liquid Carbon dioxide and (B) 0.1% DEA in methanol, flow rate=80 mL/min)to give first eluting fraction (I-148-a) and second eluting fraction(I-148-b). (*Absolute stereochemistry not determined.)

I-148-a: MS (ES): m/z: 566.5 [M−H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 11.46(s, 1H), 10.53 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.81 (s, 1H), 7.70(s, 1H), 7.48 (s, 1H), 6.70-6.66 (m, 1H), 6.17 (s, 1H), 4.34-4.30 (m,1H), 4.09-4.03 (m, 2H), 3.67 (bs, 1H), 3.40 (s, 3H), 2.95 (bs, 1H), 2.24(s, 3H), 2.19 (s, 3H), 1.91 (bs, 2H), 1.55 (bs, 2H), 1.25 (s, 9H).

I-148-b: MS (ES): m/z: 568.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 11.46(s, 1H), 10.55 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.81 (s, 1H), 7.69(s, 1H), 7.48 (s, 1H), 6.68 (bs, 1H), 6.17 (s, 1H), 4.34-4.30 (m, 1H),4.09-4.03 (m, 2H), 3.67 (bs, 1H), 3.40 (s, 3H), 2.97-2.95 (m, 1H), 2.19(s, 3H), 2.11 (s, 3H), 1.91 (bs, 2H), 1.46 (bs, 2H), 1.25 (s, 9H).

Example 149:(S)—N-(4-((7-chloro-2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 149.1. To a solution of 1H-pyrazol-3-amine (10.0g, 120.35 mmol, 1.0 equiv) and hexane-2,5-dione (13.74 g, 120.35 mmol,1.0 equiv) in toluene (100 mL), was added acetic acid (catalytic). Thereaction mixture was refluxed with a Dean-Stark trap to remove water.The reaction mixture was cooled to rt and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 25% ethyl acetate in hexane) to afford 149.1.MS (ES): m/z 162.2 [M+H]⁺.

Synthesis of compound 149.2. A mixture of 149.1 (15 g, 93.05 mmol, 1.0equiv), 19.3 (18.56 g, 111.66 mmol, 1.2 equiv) and cesium carbonate(60.48 g, 186.01 mmol, 2.0 equiv) in DMF (150 mL) was stirred at 80-90°C. for 5 h. It was poured over ice-water, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 17% ethyl acetate in hexane) to afford 149.2.MS (ES): m/z 232.3 [M+H]⁺.

Synthesis of compound 149.3. To a solution of 149.2 (10 g, 43.23 mmol,1.0 equiv) in THF (100 mL), was added n-butyl lithium (2.5 M in hexane)(22.5 mL, 56.19 mmol, 1.3 equiv) dropwise at −78° C. and stirred for 1h. To the solution was added DMF (7.3 mL, 95.10 mmol, 2.2 equiv) and thereaction mixture was stirred at −78° C. for 30-40 min. A saturatedaqueous solution of ammonium chloride was added carefully to quench thereaction. The mixture was warmed to room temperature and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford 149.3.

Synthesis of compound 149.4. To a solution of 149.3 (3.5 g, 13.50 mmol,1.0 equiv) in THF (50 mL), was added sodium borohydride (0.62 g, 16.2mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred at 0° C. for1 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 149.4.

Synthesis of compound 149.5. To a solution of 149.4 (2.5 g, 9.57 mmol,1.0 equiv) and triethylamine (4.0 mL, 28.71 mmol, 3.0 equiv) indichloromethane (40 mL) at 0° C. was added MSCl (1.1 mL, 14.35 mmol, 1.5equiv). The reaction mixture was allowed to warm to rt and stirred for 1h. It was poured over ice-water, stirred and extracted withdichloromethane. The combined organic layers were washed with saturatedaqueous sodium bicarbonate followed by brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 15% ethyl acetate in hexane) to afford 149.5. MS (ES): m/z280.7 [M+H]⁺.

Synthesis of compound 149.6. To a solution of 149.6 (2.0 g, 7.15 mmol,1.0 equiv) in acetonitrile (40 mL) was added potassium carbonate (1.97g, 14.3 mmol, 2.0 equiv) followed by addition of trimethylsilyl cyanide(1.415 g, 14.3 mmol, 2.0 equiv). The reaction mixture was stirred at 80°C. for 5 h. It was poured over ice-water, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 25% ethyl acetate in hexane) to afford 149.6.MS (ES): m/z 271.3 [M+H]⁺.

Synthesis of compound 149.7. To a solution of 149.6 (1.0 g, 3.70 mmol,1.0 equiv) in DMF (15 mL), was added sodium hydride (0.592 g, 14.8 mmol,4.0 equiv) at 0° C. and stirred for 20 min. To the mixture was addedmethyl iodide (2.1 g, 14.8 mmol, 4.0 equiv) and it was allowed to warmto rt with stirring for 30 min. It was poured into ice, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 22% ethyl acetate inhexane) to afford 149.7. MS (ES): m/z 299.4 [M+H]⁺.

Synthesis of compound 149.8. To a suspension of 149.7 (0.3 g, 1.01 mmol,1.0 equiv) in water (10 mL) was added trifluoroacetic acid (3 mL) andstirred at 120° C. for 30 min. The reaction mixture was poured into amixture of ice-saturated aqueous solution of sodium bicarbonate, stirredand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.4% methanol indichloromethane) to afford 149.8. MS (ES): m/z 221.3 [M+H]⁺.

Synthesis of I-149. Compound I-149 was prepared from compound 142.2 and149.8 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in dichloromethane) to afford I-149. MS(ES): m/z: 536.77 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56 (s, 1H),10.27 (s, 1H), 8.19-8.17 (d, J=6.0 Hz, 1H), 8.10 (s, 1H), 7.64 (s, 1H),6.80 (s, 1H), 6.66-6.64 (m, 1H), 5.30 (bs, 1H), 4.18-4.06 (m, 2H), 3.94(s, 3H), 3.88-3.85 (m, 2H), 2.28-2.24 (m, 2H), 2.03 (s, 3H), 1.83 (s,6H).

Example 150:trans-N-(4-((7-chloro-2-((1-(3-methoxycyclobutyl)-5-(perfluoroethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 150.1. Compound 150.1 was prepared from compound56.4 following the procedure described in the synthesis of compound28.5. The crude product was used in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 4.73-4.69 (m, 1H), 3.63-3.60(m, 1H), 3.29 (s, 3H), 3.03 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.26 (m,2H).

Synthesis of compound 150.2 and 150.3. To a solution of 126.4 (2.4 g,8.60 mmol, 1.0 equiv) and 150.1 (2.32 g, 12.89 mmol, 1.5 equiv) in DMF(25 mL) was added cesium carbonate (5.59 g, 17.2 mmol, 2.0 equiv) andreaction mixture was heated at 80-90° C. for 12 h. It was poured overice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,8-10% ethyl acetate in hexane) to afford mixture of 150.2 and 150.3(88:12). The mixture was used in the next step without furtherpurification.

Synthesis of compound 150.5. Compound 150.5 was prepared from the abovemixture of 150.2 and 150.3 following the procedure described in thesynthesis of compound 120.6. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 28-30% ethyl acetate inhexane) to afford 150.5. MS (ES): m/z 286.3 [M+H]⁺.

Synthesis of I-150. Compound I-150 was prepared from compound 142.2 and150.5 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.7% methanol in dichloromethane) to afford I-150. MS(ES): m/z: 601.85 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.66 (s, 1H),10.60 (s, 1H), 8.20-8.19 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.65 (s, 1H),7.38 (s, 1H), 6.66 (d, J=3.6 Hz, 1H), 5.05 (bs, 1H), 4.23 (bs, 1H), 3.99(s, 3H), 3.20 (s, 3H), 2.79-2.77 (m, 2H), 2.44 (bs, 2H), 2.04 (s, 3H).

Example 151:(R)—N-(4-((2-((5-(tert-butyl)-4-fluoro-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropane-carboxamide

Synthesis of I-151. Compound I-151 was prepared from compound 133.2 and138.7 following the procedure described in the synthesis of compoundI-136. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.5% methanol in dichloromethane). MS (ES): m/z:535.49 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.81 (s, 1H), 9.37 (s, 1H),8.20-8.17 (m, 1H), 7.95-7.94 (d, J=2.4 Hz, 1H), 7.68-7.54 (m, 2H),6.72-6.67 (m, 1H), 5.27-5.26 (m, 1H), 4.12-4.00 (m, 2H), 3.95-3.78 (m,2H), 3.65 (s, 3H), 2.26-2.20 (m, 1H), 1.99-1.94 (m, 1H), 1.43 (s, 9H),1.24-1.20 (m, 1H), 0.76-0.75 (m, 4H).

Example 152:(S)—N-(4-((2-((5-(tert-butyl)-4-fluoro-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-152. Compound I-152 was prepared from compound 133.2 and139.3 following the procedure described in the synthesis of compoundI-136. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.6% methanol in dichloromethane). MS (ES): m/z:535.50 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.83 (s, 1H), 9.39 (s, 1H),8.21-8.18 (m, 1H), 7.96 (bs, 1H), 7.69-7.64 (m, 2H), 6.70-6.69 (m, 1H),5.27-5.26 (m, 1H), 4.13-4.01 (m, 2H), 3.90-3.78 (m, 2H), 3.66 (s, 3H),2.22-2.21 (m, 1H), 2.00-1.95 (m, 1H), 1.44 (s, 9H), 1.25-1.19 (m, 1H),0.77 (bs, 4H).

Example 153:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-153. Compound I-153 was prepared from compound 147.9 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:541.87 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.56 (s, 1H), 10.09 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.48-7.21 (m,1H), 6.66-6.64 (m, 1H), 6.57 (s, 1H), 5.31-5.23 (s, 1H), 4.11-4.08 (m,2H), 3.97-3.83 (m, 2H), 3.79 (s, 3H), 2.38-2.33 (m, 1H), 2.27-2.22 (m,1H), 2.04 (s, 3H), 1.41 (s, 9H).

Example 154:(S)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-ethyl-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 154.1. To a solution of 98.2 (2.0 g, 11.62 mmol,1.0 equiv) in THF (20 mL), was added diisopropylamine (4.0 mL, 29.05mmol, 2.5 equiv), stirred and cooled to −78° C. followed by addition ofn-butyl lithium (2.5 M in hexane) (11.6 mL, 29.05 mmol, 2.5 equiv). Thereaction mixture was stirred at −78° C. for 1 h. Iodoethane (1.1 mL,13.94 mmol, 1.2 equiv) was added and the reaction mixture was stirred at−60° C. to −70° C. for 2 h. Aqueous solution of ammonium chloride wasadded carefully to quench the reaction. The mixture was warmed to roomtemperature and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 20%ethyl acetate in hexane) to afford 154.1. MS (ES): m/z 201.2 [M+H]⁺.

Synthesis of compound 154.2. To a solution of 154.1 (1.3 g, 6.49 mmol,1.0 equiv) in methanol (5 mL), was added concentrated hydrochloric acid(2.5 mL). The reaction mixture was refluxed for 2 h. Most solvent wasremoved under reduced pressure. The residue was added ice-water and pHof the mixture was adjusted to 9-10 by addition of 3 N aqueous solutionof sodium hydroxide. The mixture is extracted with diethyl ether. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 30% ethyl acetate in hexane) to afford 154.2. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.76 (bs, 1H), 6.02 (bs, 2H), 2.64-2.59 (q, 2H),1.17-1.13 (t, 3H).

Synthesis of compound 154.3. To the suspension of potassium persulfate(3.34 g, 12.4 mmol, 2.8 equiv) in concentrated sulfuric acid (5 mL) wasadded 154.2 (0.7 g, 4.43 mmol, 1.0 equiv). The reaction mixture wasstirred at room temperature for 4 h. It was poured over crushed ice,stirred, neutralized with saturated aqueous sodium bicarbonate solutionand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 10% ethyl acetate inhexane) to afford 154.3. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.47 (bs, 1H),3.00-2.94 (q, 2H), 1.35-1.32 (t, 3H).

Synthesis of compound 154.4. To a solution of 154.3 (0.370 g, 1.97 mmol,1.0 equiv) in acetonitrile (5 mL) was added aqueous methylamine solution(40%) (0.2 mL, 2.95 mmol, 1.5 equiv) dropwise at 0° C. The reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas poured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 12% ethyl acetate in hexane) to afford 154.4. (0.365 g,93.18%). ¹H NMR (CDCl₃, 400 MHz): δ 7.78 (s, 1H), 6.55-6.54 (d, J=5.6Hz, 1H), 2.72-2.70 (q, 2H), 2.67-2.66 (d, 3H), 1.12-1.08 (t, 3H).

Synthesis of compound 154.5. A mixture of 154.4 (0.365 g, 1.83 mmol, 1.0equiv), Int-1 (0.334 g, 2.20 mmol, 1.2 equiv) and sodium carbonate(0.387 g, 3.66 mmol, 2.0 equiv) in DMF (5 mL) was stirred at 90° C. for12 h. It was cooled to room temperature, transferred into ice-water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 50% ethyl acetate inhexane to afford 154.5. MS (ES): m/z 332.3 [M+H]⁺.

Synthesis of compound 154.6. A mixture of compound 154.5 (0.229 g, 0.691mmol, 1.0 equiv), iron powder (0.193 g, 3.45 mmol, 5.0 equiv) andammonium chloride (0.193 g, 3.15 mmol, 5.0 equiv) in ethanol:water (8:2,6 mL) was stirred at 80° C. for 2 h. It was filtered through a pad ofCelite® and washed with ethanol. The filtrate was concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.0% methanol indichloromethane) to afford 154.6. MS (ES): m/z 302.3 [M+H]⁺.

Synthesis of compound 154.7. Compound 154.7 was prepared from compound154.6 following the procedure described in the synthesis of compound148.8. The product was triturated with hexane to afford 154.7. MS (ES):m/z: 344.4 [M+H]⁺.

Synthesis of compound 154.8. Compound 154.8 was prepared from compound154.7 following the procedure described in the synthesis of compound148.9. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.3% methanol in dichloromethane). MS (ES): m/z 391.2[M+H]⁺.

Synthesis of I-154. Compound I-154 was prepared from compound 149.8 and154.8 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.4% methanol in dichloromethane). MS (ES): m/z: 530.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.51 (s, 1H), 10.01 (s, 1H),8.17-8.15 (d, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 6.79 (s, 1H),6.63-6.61 (m, 1H), 5.32-5.25 (m, 1H), 4.16-4.12 (m, 2H), 3.85 (s, 5H),2.85-2.80 (m, 2H), 2.30-2.22 (m, 1H), 2.03 (s, 3H), 1.82 (bs, 6H), 1.55(bs, 1H), 1.16-1.13 (t, 3H).

Example 155:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 155.1. To solution of 142.1 (1.0 g, 2.86 mmol, 1.0equiv) in methanol (7 mL) and N-methyl-2-pyrrolidone (15 mL) was addedas solution of sodium methoxide in methanol (25% w/w, 8 mL, 37.18 mmol,13 equiv) and copper iodide (0.119 g, 0.629 mmol, 0.22 equiv). Thereaction mixture was stirred at 140° C. in a sealed tube for 4 h. It wascooled to room temperature, transferred into ice-water, and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5% methanol indichloromethane as eluant). MS (ES): m/z: 304.3 [M+H]⁺.

Synthesis of compound 155.2. To a solution of 155.1 (0.050 g, 0.164mmol, 1.0 equiv) in acetonitrile (5 mL) was added sulfuryl chloride(0.49 mL, 6.06 mmol, 37 equiv) at 0° C. and reaction mixture was stirredfor 15 min. The reaction mixture was transferred into saturated aqueoussodium bicarbonate solution, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3.0% methanol in dichloromethane) to afford 155.2. MS(ES): m/z 306.7 [M+H]⁺.

Synthesis of compound 155.3. To a solution of 155.2 (0.025 g, 0.081mmol, 1.0 equiv) in dichloromethane (2 mL) was added pyridine (0.03 mL)at 0° C. followed by acetic anhydride (0.019 mL, 0.202 mmol, 2.5 equiv)and reaction mixture was stirred for 5 min. The reaction mixture wastransferred into saturated aqueous sodium bicarbonate solution, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.8% methanol indichloromethane) to afford 155.3. MS (ES): m/z 348.7 [M+H]⁺.

Synthesis of I-155. Compound I-155 was prepared from compound 24.1 and155.3 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.9% methanol in dichloromethane). MS (ES): m/z: 521.8[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.25 (s, 1H), 9.46 (s, 1H),8.18-8.17 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 6.66-6.64 (m,1H), 6.55 (s, 1H), 5.23 (m, 1H), 4.14-4.08 (m, 2H), 3.93 (s, 3H),3.89-3.84 (m, 2H), 2.38-2.28 (m, 3H), 2.07 (s, 3H), 1.59 (bs, 2H), 1.43(s, 9H).

Example 156:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-156. Compound I-156 was prepared from compound 20.1 and155.3 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.0% methanol in dichloromethane). MS (ES): m/z:521.49 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56 (s, 1H), 9.82 (s, 1H),8.19-8.17 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 6.66-6.65 (d,1H), 6.55 (s, 1H), 5.26 (bs, 1H), 4.09 (bs, 2H), 3.96 (s, 3H), 3.90-3.83(m, 3H), 2.34-2.24 (m, 2H), 2.04 (s, 3H), 2.00 (bs, 2H), 1.41 (s, 9H).

Example 157:(R)—N-(4-((7-chloro-2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-157. Compound I-157 was prepared following the proceduresdescribed in the synthesis of compound I-149. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 3.5% methanolin dichloromethane). MS (ES): m/z: 536.77 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz): δ 10.58 (s, 1H), 10.30 (s, 1H), 8.19-8.17 (d, J=6.0 Hz, 1H), 8.11(s, 1H), 7.64 (s, 1H), 6.80 (s, 1H), 6.66-6.64 (m, 1H), 5.30 (bs, 1H),4.16-4.10 (m, 2H), 3.94 (s, 3H), 3.88-3.84 (m, 2H), 2.29-2.24 (m, 2H),2.03 (s, 3H), 1.83 (s, 6H).

Example 158:(R)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-ethyl-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-158. Compound I-158 was prepared from compound 154.8 and157.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES): m/z:530.49 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.54 (s, 1H), 10.04 (s, 1H),8.18-8.16 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 6.80 (s, 1H),6.63-6.62 (m, 1H), 5.29 (bs, 1H), 4.19-4.09 (m, 2H), 3.91-3.86 (m, 5H),2.86-2.81 (m, 2H), 2.29-2.25 (m, 1H), 2.03 (s, 3H), 1.82 (bs, 6H), 1.55(bs, 1H), 1.16-1.13 (t, 3H).

Example 159:N-(4-((7-chloro-2-((1-((1s,3s)-3-methoxycyclobutyl)-5-(perfluoroethyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 159.1 and 159.2. A mixture of 126.4 (1.2 g, 4.3mmol, 1.0 equiv), 56.8 (0.930 g, 5.16 mmol, 1.2 equiv) and cesiumcarbonate (2.8 g, 8.6 mmol, 2.0 equiv) in DMF (8 mL) was stirred at80-90° C. for 12 h. It was poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford a mixture (91:8) of 159.1 and 159.2. It wasused in the next step without further purification.

Synthesis of compound 159.3. Compound 159.3 was prepared from the abovemixture of 159.1 and 159.2 following the procedure described in thesynthesis of compound 120.6. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 28-30% ethyl acetate inhexane) to afford 159.3. MS (ES): m/z 286.3 [M+H]⁺.

Synthesis of I-159. Compound I-159 was prepared from compound 159.3 and142.2 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.6% methanol in dichloromethane. MS (ES): m/z: 601.88[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.69 (s, 1H), 10.59 (s, 1H),8.20-8.18 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H),6.66 (d, J=3.6 Hz, 1H), 4.65-4.61 (m, 1H), 3.98 (s, 3H), 3.83-3.80 (m,1H), 3.20 (s, 3H), 2.79 (bs, 2H), 2.52 (bs, 2H), 2.04 (s, 3H).

Example 160:(R)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-160. Compound I-160 was prepared from compound 147.9 and157.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.8% methanol in dichloromethane). MS (ES): m/z:552.46 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.59 (s, 1H), 10.36 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.49-7.23 (m,1H), 7.09-7.06 (d, J=7.6 Hz, 1H), 6.66-6.64 (m, 1H), 5.35-5.30 (m, 1H),3.99-3.95 (m, 2H), 3.90-3.84 (m, 2H), 3.81 (s, 3H), 2.28-2.23 (m, 2H),2.03 (s, 3H), 1.83-1.82 (d, 3H), 1.55 (bs, 3H).

Example 161:(S)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-161. Compound I-161 was prepared from compound 147.9 and149.8 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.8% methanol in dichloromethane). MS (ES): m/z:552.85 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.59 (s, 1H), 10.36 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.49-7.23 (m,1H), 7.09-7.06 (d, J=7.6 Hz, 1H), 6.66-6.64 (m, 1H), 5.35-5.30 (m, 1H),4.18-4.10 (m, 2H), 3.99-3.96 (m, 2H), 3.81 (s, 3H), 2.33-2.26 (m, 2H),2.03 (s, 3H), 1.83-1.82 (d, 3H), 1.55 (bs, 3H).

Example 162:N-(4-((2-((5-(tert-butyl)-1-((1S,2R)-2-hydroxycyclopentyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideandN-(4-((2-((5-(tert-butyl)-1-((1R,2S)-2-hydroxycyclopentyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-162.1. A mixture of compound 19.2 (105 g,46.02 mmol, 1.0 equiv), 6-oxabicyclo[3.1.0]hexane (5.81 g, 69.02 mmol,1.5 equiv) and cesium carbonate (44.86 g, 138.06 mmol, 3.0 equiv) in DMF(100 mL) was stirred at 80° C. for 16 h. The reaction mixturetransferred into water and product was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 5-10% ethyl acetate in hexane) to afford (±)-162.1. MS(ES): m/z 302.4 [M+H]⁺.

Synthesis of compound (±)-162.2. To a solution of compound (±)-162.1(1.6 g, 5.31 mmol, 1.0 equiv) and 4-nitrobenzoic acid (1.77 g, 10.62mmol, 2.0 equiv) in toluene (35 mL) at 0° C. was addeddiphenylphosphoryl azide (3.17 g, 7.96 mmol, 1.5 equiv) followed bydiethylazodicarboxylate (1.38 g, 7.96 mmol, 1.5 equiv). The reactionmixture was allowed to warm to rt and stirred for 2 h. It was pouredinto ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 4%ethyl acetate in hexane) to afford (±)-162.2. MS (ES): m/z 451.4 [M+H]⁺.

Synthesis of compound (±)-162.3. To a solution of (±)-162.2 (0.8 g, 1.78mmol, 1.0 equiv) in methanol (20 mL) was added potassium carbonate (1.96g, 14.24 mmol, 8.0 equiv) and reaction mixture was stirred at roomtemperature for 1 h. It was poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane)to afford (±)-162.3. MS (ES): m/z 302.4 [M+H]⁺.

Synthesis of compound (±)-162.4. To a solution of (±)-162.3 (0.5 g, 1.66mmol, 1.0 equiv) in DMF (10 mL), was added sodium hydride (0.132 g, 3.32mmol, 2.0 equiv) at 0° C. and stirred for 20 min followed by theaddition of benzyl bromide (0.3 mL, 2.49 mmol, 1.5 equiv). The reactionmixture was stirred at room temperature for 30 min. It was transferredinto ice, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 5%ethyl acetate in hexane) to afford (±)-162.4. MS (ES): m/z 392.5 [M+H]⁺.

Synthesis of compound (±)-162.5. Compound (±)-162.5 was prepared from(±)-162.4 following the procedure described in the synthesis of compound120.6. The residue was purified by flash column chromatography on silicagel (CombiFlash®, 28-30% ethyl acetate in hexane). MS (ES): m/z 314.4[M+H]⁺.

Synthesis of compound (±)-162.6. Compound (±)-162.6 was prepared fromcompound (±)-162.5 and 148.8 following the procedure described in thesynthesis of compound 1-108. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 3.0% methanol indichloromethane). MS (ES): m/z: 595.7 [M+H]⁺.

Synthesis of compound I-162-a and I-162-b. To a solution of (±)-162.6(0.160 g, 0.269 mmol, 1.0 equiv) in dichloromethane (5 mL) was addedtriflic acid (0.6 mL) at 0° C. and stirred for 15 min. The reactionmixture was transferred into ice-water and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford the racemate. The enantiomers were separatedby HPLC (CHIRALPAK IH (250 mm×21 mm, 5 μm); elute: (A) 0.1% DEA inn-hexane, (B) 0.1% DEA in 2-propanol:methanol (30:70); flow rate=18mL/min.) to afford first eluting fraction (I-162-a) and second elutingfraction (I-162-b). (*Absolute stereochemistry not determined.)

I-162-a: MS (ES): m/z: 505.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53(s, 1H), 9.83 (s, 1H), 8.18-8.16 (d, J=6.0 Hz, 1H), 7.96-7.95 (d, J=2.0Hz, 1H), 7.66 (s, 1H), 7.63-7.62 (d, J=2.4 Hz, 1H), 6.66-6.64 (m, 1H),6.56 (s, 1H), 5.03-5.02 (d, 1H), 4.60-4.45 (m, 2H), 3.66 (s, 3H),2.13-2.07 (m, 1H), 2.03 (s, 3H), 1.99-1.91 (m, 1H), 1.89-1.83 (m, 1H),1.82-1.75 (m, 2H), 1.66-1.59 (m, 1H), 1.41 (s, 9H).

I-162-b: MS (ES): m/z: 505.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53(s, 1H), 9.83 (s, 1H), 8.18-8.16 (d, J=6.0 Hz, 1H), 7.96-7.95 (d, J=2.4Hz, 1H), 7.66 (s, 1H), 7.63-7.62 (d, J=2.4 Hz, 1H), 6.66-6.64 (m, 1H),6.56 (s, 1H), 5.03-5.02 (d, 1H), 4.58-4.46 (m, 2H), 3.66 (s, 3H),2.13-2.07 (m, 1H), 2.03 (s, 3H), 1.99-1.91 (m, 1H), 1.89-1.83 (m, 1H),1.82-1.75 (m, 2H), 1.64-1.59 (m, 1H), 1.41 (s, 9H).

Example 163:(S)—N-(4-((2-((5-(tert-butyl)-1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropane-carboxamideand(R)—N-(4-((2-((5-(tert-butyl)-1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound (±)-163.1. To a suspension of sodium hydride (2.2g, 55.48 mmol, 1.0 equiv) in THF (20 mL) was added solution of2-methylpropane-1,3-diol (5.0 g, 55.48 mmol, 1.0 equiv) in THF (25 mL)and stirred at 70° C. for 1 h. To the mixture was added benzyl bromide(6.6 mL, 55.48 mmol, 1.0 equiv) and stirred at 70° C. for 2 h. It wascooled to rt and poured into ice, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20-25% ethyl acetate in hexane) to afford(±)-163.1. MS (ES): m/z 181.2 [M+H]⁺.

Synthesis of compound (±)-163.2. Compound (±)-163.2 was prepared fromcompound (±)-163.1 following the procedure described in the synthesis ofcompound 28.5. The crude product was used in the next step withoutfurther purification.

Synthesis of compound (±)-163.3. Compound (±)-163.3 was prepared fromcompound (±)-163.2 and 19.2 following the procedure described in thesynthesis of compound 28.7. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5-3.0% ethyl acetate inhexane). MS (ES): m/z 380.5 [M+H]⁺.

Synthesis of compound (±)-163.4. Compound (±)-163.4 was prepared fromthe above mixture of (±)-163.3 following the procedure described in thesynthesis of compound 120.6. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 1.2% methanol indichloromethane). MS (ES): m/z 302.4 [M+H]⁺.

Synthesis of compound (±)-163.5. Compound (±)-163.5 was prepared fromcompound (±)-163.4 and 133.2 following the procedure described in thesynthesis of compound I-108. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 2.6% methanol indichloromethane). MS (ES): m/z: 609.5 [M+H]⁺.

Synthesis of compound I-163-a and I-163-b. To a solution of (±)-163.5(0.110 g, 0.180 mmol, 1.0 equiv) in dichloromethane (10 mL) was addedtriflic acid (0.4 mL) at 0° C. and stirred for 5 min. The reactionmixture was transferred into a mixture of ice and saturated aqueoussodium bicarbonate and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,4.0% methanol in dichloromethane) to afford the racemate product. Theenantiomers were separated by SFC (column CHIRAL-CEL OX-H (250 mm*21 mm,5 μm, mobile phase: (A) liquid carbon dioxide and (B) 0.3% DEA in2-propanol:acetonitrile (50:50); flow rate=80 mL/min) to afford firsteluting fraction (I-163-a) and second eluting fraction (I-163-b).

I-163-a: MS (ES): m/z: 519.5 [M+H]⁺, LCMS purity: 98.10%, HPLC purity:95.48%, Chiral HPLC: 100%, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H),9.83 (s, 1H), 8.19-8.17 (d, J=6.0 Hz, 1H), 7.95-7.94 (d, J=2.4 Hz, 1H),7.62-7.59 (m, 2H), 6.70-6.68 (m, 1H), 6.59 (s, 1H), 4.67-4.66 (m, 1H),4.15-4.10 (m, 1H), 3.90-3.84 (m, 1H), 3.66 (s, 3H), 3.50 (bs, 2H),2.70-2.67 (m, 1H), 2.01-1.88 (m, 1H), 1.39 (s, 9H), 1.25-1.24 (d, 3H),0.90-0.84 (m, 2H), 0.81-0.74 (m, 2H).

I-163-b: MS (ES): m/z: 519.5 [M+H]⁺, LCMS purity: 100%, HPLC purity:99.41%, Chiral HPLC: 100%, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H),9.83 (s, 1H), 8.19-8.17 (d, J=6.0 Hz, 1H), 7.95-7.94 (d, J=2.4 Hz, 1H),7.62 (bs, 2H), 6.70-6.68 (m, 1H), 6.63 (s, 1H), 4.67-4.66 (m, 1H),4.15-4.10 (m, 1H), 3.90-3.84 (m, 1H), 3.66 (s, 3H), 3.50 (bs, 2H),2.67-2.58 (m, 1H), 1.99-1.95 (m, 1H), 1.39 (s, 9H), 1.25-1.24 (d, 3H),0.90-0.84 (m, 2H), 0.81-0.74 (m, 2H).

Example 164:N-(4-((2-((5-(tert-butyl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 164.1. Concentrated sulfuric acid (60 mL, 6volumes) was added dropwise to potassium persulfate (54.31 g, 201.15mmol, 2.8 equiv) at room temperature and stirred for 15 min. To themixture was added 19.1 (10 g, 71.84 mmol, 1.0 equiv) in portionsmaintaining temperature 30-40° C. The reaction mixture was stirred atroom temperature for 30 min. It was poured over crushed ice, stirred andbasified with saturated aqueous sodium bicarbonate and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 15% ethyl acetate in hexane) to afford 164.1.¹H NMR (DMSO-d₆, 400 MHz): δ 11.20 (s, 1H), 6.26 (s, 1H), 1.29 (s, 9H).

Synthesis of compound 164.2. Compound 164.2 was prepared from compound164.2 and 37.3 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 15-20% ethyl acetate in hexane). MS (ES):m/z 266.3 [M+H]⁺.

Synthesis of compound 164.3. To a solution of 164.2 (0.200 g, 0.753mmol, 1.0 equiv) in ethanol:water (2:1, 5 mL) was added iron powder(0.210 g, 3.765 mmol, 5 equiv) followed by ammonium chloride (0.203 g,3.765 mmol, 5 equiv). The reaction mixture was heated at 50° C. for 30min. It was poured over ice-water, filtered and product was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to obtain 164.3. MS (ES): m/z 236.3 [M+H]⁺.

Synthesis of I-164. Compound I-164 was prepared from compound 164.3 and133.2 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES): m/z: 543.9[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.83 (s, 1H), 9.88 (s, 1H),8.19-8.17 (d, J=5.6 Hz, 1H), 7.95-7.94 (d, J=2.4 Hz, 1H), 7.63 (bs, 2H),6.77-6.68 (m, 1H), 6.57 (s, 1H), 4.70 (s, 2H), 4.57 (s, 2H), 3.66 (s,3H), 2.80-2.67 (m, 3H), 1.99-1.91 (m, 2H), 35 (s, 9H), 1.19-1.16 (m,1H), 0.88-0.86 (m, 4H).

Example 165:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-0)oxy)pyridin-2-yl)-3-methoxyazetidine-1-carboxamide

Synthesis of compound 165.1. To a solution of 14.3 (2.0 g, 9.99 mmol,1.0 equiv) and triethylamine (4.2 mL, 29.97 mmol, 3.0 equiv) in THF (20mL) at 0° C. was added phenyl chloroformate (4.67 g, 29.97 mmol, 3.0equiv) dropwise. The reaction mixture was allowed to warm to rt andstirred for 3 h. It was transferred into water and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was used in the next step without furtherpurification. MS (ES): m/z 321.3 [M+H]⁺.

Synthesis of compound 165.2. To a solution of 165.1 (3.0 g, 9.36 mmol,1.0 equiv) and triethylamine (12.5 mL, 84.24 mmol, 9.0 equiv) in DMF (20mL) at 0° C. was added 3-methoxyazetidine (1.06 g, 12.17 mmol, 1.3equiv) dropwise. The reaction mixture stirred at room temperature for 16h. It was transferred into water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in dichloromethane) to afford 165.2 MS (ES):m/z 314.3 [M+H]⁺.

Synthesis of compound 165.3. A mixture of compound 165.3 (1.1 g, 3.51mmol, 1.0 equiv) and 10% palladium on carbon (0.5 g) in methanol (10 mL)was stirred at rt under hydrogen atmosphere (1 atm) for 3 h. Thereaction mixture was filtered through a pad of Celite® and washed withmethanol. The filtrate was concentrated under reduced pressure to obtain165.3. MS (ES): m/z 224.2 [M+H]⁺.

Synthesis of compound 165.4. Compound 165.4 was prepared from compound165.3 and 96.3 following the procedure described in the synthesis ofcompound 96.4. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.8% methanol in dichloromethane). MS (ES):m/z 375.3 [M+H]⁺.

Synthesis of compound 165.5. Compound 165.5 was prepared from compound165.4 following the procedure described in the synthesis of compoundInt-4. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES): m/z 345.5[M+H]⁺.

Synthesis of compound 165.6. Compound 165.6 was prepared from compound165.5 following the procedure described in the synthesis of compound102.1. The product was purified by trituration in hexane. MS (ES): m/z:387.4 [M+H]⁺.

Synthesis of compound 165.7. Compound 165.7 was prepared from compound165.6 following the procedure described in the synthesis of compound102.2. The residue was purified by flash column chromatography on silicagel (CombiFlash®, 2.4% methanol in dichloromethane). MS (ES): m/z 389.8[M+H]⁺.

Synthesis of I-165. Compound I-165 was prepared from compound 165.7 and24.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.0% methanol in dichloromethane). MS (ES): m/z:563.05 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 9.89 (s, 1H), 9.20 (s, 1H),8.11-8.10 (d, J=5.6 Hz, 1H), 7.96-7.95 (d, J=2.4 Hz, 1H), 7.63-7.62 (d,J=2.4 Hz, 1H), 7.47 (bs, 1H), 6.60-6.58 (m, 2H), 5.77 (s, 1H), 5.26 (bs,1H), 4.13-4.07 (m, 5H), 3.88-3.83 (m, 2H), 3.75-3.73 (m, 2H), 3.68 (s,3H), 3.19 (s, 3H), 2.27-2.24 (m, 1H), 1.41 (s, 9H).

Example 166:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-methoxyazetidine-1-carboxamide

Synthesis of I-166. Compound I-166 was prepared from compound 165.7 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.0% methanol in dichloromethane). MS (ES): m/z:562.64 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 9.88 (s, 1H), 9.20 (s, 1H),8.10-8.09 (d, J=5.6 Hz, 1H), 7.94-7.94 (d, J=2.4 Hz, 1H), 7.62-7.61 (d,J=2.4 Hz, 1H), 7.46 (bs, 1H), 6.59-6.56 (m, 2H), 5.76 (s, 1H), 5.27-5.25(m, 1H), 4.11-4.06 (m, 5H), 3.87-3.82 (m, 2H), 3.74-3.72 (m, 2H), 3.66(s, 3H), 3.18 (s, 3H), 2.27-2.21 (m, 1H), 1.40 (s, 9H).

Example 167:(R)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-167. Compound I-167 was prepared from compound 155.3 and157.7 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.4% methanol in dichloromethane). MS (ES): m/z: 533.1[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56 (s, 1H), 10.07 (s, 1H),8.19-8.18 (d, J=5.6 Hz, 1H), 7.68 (s, 1H), 7.09-7.08 (d, J=5.6 Hz, 1H),6.84-6.80 (m, 1H), 6.67-6.65 (m, 1H), 5.28 (bs, 1H), 4.19-4.11 (m, 2H),4.01-3.95 (m, 2H), 3.91 (s, 3H), 3.84 (s, 3H), 3.40-3.35 (m, 2H), 2.04(s, 3H), 1.83 (bs, 6H).

Example 168:(S)—N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-168. Compound I-168 was prepared from compound 155.3 and149.8 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in dichloromethane). MS (ES): m/z: 533.1[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56 (s, 1H), 10.06 (s, 1H),8.18-8.16 (d, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.08-7.06 (d, J=5.6 Hz, 1H),6.83-6.81 (d, J=6.4 Hz, 1H), 6.66-6.64 (m, 1H), 5.28 (bs, 1H), 4.17-4.08(m, 2H), 4.00-3.93 (m, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.41-3.34 (m,2H), 2.03 (s, 3H), 1.82 (bs, 6H).

Example 169:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamideand(R)—N-(4-((2-((5-(tert-butyl)-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound (±)-169.2. Compound (±)-169.2 was prepared fromcompound (±)-169.1 following the procedure described in the synthesis ofcompound 28.5. The crude product was used in the next step withoutfurther purification. ¹H NMR (DMSO-d₆, 400 MHz): δ 5.24 (bs, 1H),3.55-3.51 (m, 2H), 3.48-3.39 (m, 2H), 3.24 (s, 3H), 2.12 (bs, 2H), 1.41(s, 9H).

Synthesis of compound (±)-169.3. A mixture of 19.2 (10 g, 46.02 mmol,1.0 equiv), (±)-169.2 (18.31 g, 69.02 mmol, 1.5 equiv) and cesiumcarbonate (37.50 g, 115.05 mmol, 2.5 equiv) in DMF (100 mL) was stirredat 100° C. for 12 h. It was poured over ice-water, stirred and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10-12% ethyl acetate inhexane) to afford (±)-169.3. MS (ES): m/z 387.5 [M+H]⁺.

Synthesis of compound (±)-169.4. To a solution of (±)-169.3 (3.3 g, 8.54mmol, 1.0 equiv) in THF (35 mL), was added lithium aluminum hydridesolution (1 M in THF) (51.2 mL, 51.24 mmol, 6.0 equiv) at 0° C. Thereaction mixture was stirred at 70° C. for 2 h. It was cooled to 0° C.and carefully quenched by saturated aqueous sodium sulfate. The reactionmixture was filtered through a pad of Celite® and washed with diethylether. The filtrate was dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 60% ethylacetate in hexane) to afford (±)-169.4. MS (ES): m/z 301.5 [M+H]⁺.

Synthesis of compound 169.5 and 169.6. The racemate was prepared from(±)-163.3 following the procedure described in the synthesis of compound120.6. The residue was purified by flash column chromatography on silicagel (CombiFlash®, 7-8% methanol in dichloromethane). MS (ES): m/z 223.3[M+H]⁺. The enantiomers were separated by HPLC (column: CHIRALPAK IG(250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1%DEA in 2-propanol:methanol (50:50); flow rate=20 mL/min) to afford firsteluting fraction (169.5) and second eluting fraction (169.6). (*Absolutestereochemistry not determined.)

Synthesis of compound 169.7. To a solution of 133.1 (1.8 g, 5.27 mmol,1.0 equiv) in acetic acid (18 mL) was added aqueous hydrobromic acid(0.640 g, 7.9 mmol, 1.5 equiv) at 0° C. followed by bromine (3.37 g,21.08 mmol, 4.0 equiv). The reaction mixture was stirred for 10 min. Itwas poured into saturated aqueous sodium bicarbonate solution, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.5% methanol indichloromethane) to afford 169.7. MS (ES): m/z 389.2 [M+H]⁺.

Synthesis of I-169-a. A mixture of 169.7 (0.070 g, 0.180 mmol, 1.0equiv), 169.5 (0.040 g, 0.180 mmol, 1.0 equiv) and tripotassiumphosphate (0.076 g, 0.36 mmol, 2.0 equiv) in THF (2 mL) was degassed bybubbling argon through for 10 min. Under argon atmosphere[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.028 g, 0.036 mmol, 0.2 equiv) wasadded, again degassed for 5 min. The reaction mixture was stirred at 70°C. for 3 h. The reaction mixture was transferred into water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to afford I-169-a. MS (ES): m/z: 530.5 [M+H]⁺, ¹H NMR(DMSO-d₆, 400 MHz): 10.84 (s, 1H), 8.34 (s, 1H), 8.19-8.17 (d, J=5.6 Hz,1H), 7.95-7.94 (d, J=2.4 Hz, 1H), 7.62 (bs, 2H), 6.70-6.68 (m, 1H), 6.55(s, 1H), 5.09-5.05 (m, 1H), 3.66 (s, 3H), 3.02-2.98 (m, 1H), 2.98-2.67(m, 2H), 2.25 (bs, 5H), 2.18-2.16 (m, 1H), 1.97-1.93 (m, 1H), 1.39 (s,9H), 0.76-0.74 (m, 4H).

Synthesis of I-169-b. Compound I-169-b was prepared from compound 169.6and 169.7 following the procedure described in the synthesis of compoundI-169-a. The product was purified by preparative HPLC. MS (ES): m/z:530.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.83 (s, 1H), 8.33 (s, 1H),8.19-8.17 (d, J=5.6 Hz, 1H), 7.95-7.94 (d, J=2.4 Hz, 1H), 7.63-7.62 (m,2H), 6.70-6.68 (m, 1H), 6.55 (s, 1H), 5.09-5.05 (m, 1H), 3.66 (s, 3H),3.02-2.98 (m, 1H), 2.72-2.67 (m, 2H), 2.30 (bs, 5H), 2.18-2.16 (m, 1H),1.97-1.93 (m, 1H), 1.39 (s, 9H), 0.76-0.74 (m, 4H).

Example 170:(R)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 170.1. To a solution of 155.2 (0.045 g, 0.147mmol, 1.0 equiv) and pyridine (0.06 mL, 0.617 mmol, 4.2 equiv) indichloromethane (2 mL) at 0° C. was added cyclopropanecarbonyl chloride(0.033 mL, 0.367 mmol, 2.5 equiv). The reaction mixture was allowed towarm to rt and stirred for 15 min. It was poured over ice-water, stirredand extracted with dichloromethane. The combined organic layers werewashed with saturated aqueous sodium bicarbonate followed by brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.8% methanol indichloromethane) to afford 170.1. MS (ES): m/z 374.8 [M+H]⁺.

Synthesis of I-170. Compound I-170 was prepared from compound 170.1 and24.1 following the procedure described in the synthesis of compoundI-108. The product was purified by preparative HPLC. MS (ES): m/z: 547.5[M+H]⁺, ¹H NMR (CDCl₃, 400 MHz): 8.70 (s, 1H), 8.12-8.11 (d, J=5.6 Hz,1H), 7.92 (bs, 2H), 6.55-6.54 (d, J=3.6 Hz, 1H), 5.17-5.14 (m, 1H),4.29-4.27 (m, 1H), 4.13-4.10 (m, 2H), 4.01 (s, 3H), 3.83 (s, 3H),2.41-2.39 (m, 2H), 1.59 (bs, 2H), 1.43 (s, 9H), 1.09 (bs, 2H), 0.91-0.90(m, 2H).

Example 171:(S)—N-(4-((2-((5-(tert-butyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-171. Compound I-171 was prepared from compound 170.1 and20.1 following the procedure described in the synthesis of compoundI-108. The product was purified by preparative HPLC. MS (ES): m/z: 547.5[M+H]⁺, ¹H NMR (CDCl₃, 400 MHz): 8.70 (s, 1H), 8.12-8.11 (d, J=5.6 Hz,1H), 7.92 (bs, 2H), 6.55-6.54 (d, J=3.6 Hz, 1H), 5.17-5.14 (m, 1H),4.29-4.27 (m, 1H), 4.13-4.10 (m, 2H), 4.01 (s, 3H), 3.83 (s, 3H),2.41-2.39 (m, 2H), 1.59 (bs, 2H), 1.43 (s, 9H), 1.09 (bs, 2H), 0.91-0.90(m, 2H).

Example 172:(R)—N-(4-((2-((5-(tert-butyl)-1-(4,4-difluoro-1-methylpyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-(4,4-difluoro-1-methylpyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 172.2. To a solution of 172.1 (25 g, 98.34 mmol,1.0 equiv) in THF (250 mL), was added n-butyl lithium (2.5M in Hexane)(78.6 mL, 196.68 mmol, 2.0 equiv) at −78° C. and stirred for 1 h. Asaturated solution of ammonium chloride was added slowly to quench thereaction. The mixture was allowed to warmed to room temperature andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 3% ethyl acetate inhexane) to afford 172.2. ¹H NMR (CDCl₃, 400 MHz): δ 7.84-7.82 (d, J=8Hz, 2H), 7.41-7.39 (d, J=8 Hz, 2H), 6.11-6.07 (m, 1H), 2.49 (s, 3H).

Synthesis of compound (±)-172.4. A mixture of 172.2 (0.500 g, 2.13 mmol,1.0 equiv), 172.3 (2.03 g, 8.54 mmol, 4.0 equiv), lithium fluoride(0.165 g, 6.39 mmol, 3.0 equiv) and acetonitrile (8 mL) in a sealed tubewas stirred at 160° C. for 6 h. The reaction mixture was cooled to roomtemperature, transferred into water, and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 7% ethyl acetate in hexane) to afford (±)-172.4. MS (ES):m/z 368.3 [M+H]⁺.

Synthesis of compound (±)-172.5. To a solution of (±)-172.4 (6.1 g,16.60 mmol, 1.0 equiv) in methanol (60 mL) was added magnesium turnings(2.78 g, 116.2 mmol, 7.0 equiv) at 0° C. in portions. The reactionmixture was stirred at room temperature for 3 h. It was poured overice-water, stirred and precipitated solids were collected by filtration.The solids were dissolved in 5 N hydrochloric acid and neutralized byaddition of a saturated aqueous solution of sodium bicarbonate. Themixture was then extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 20%ethyl acetate in hexane) to afford (±)-172.5. MS (ES): m/z 214.2 [M+H]⁺.

Synthesis of compound (±)-172.6. To a solution of (±)-172.5 (2.0 g, 9.38mmol, 1.0 equiv) and pyridine (3.8 mL, 46.9 mmol, 5.0 equiv) indichloromethane (20 mL) at −10° C. was added triflic anhydride (3.9 mL,23.45 mmol, 2.5 equiv). The reaction mixture stirred at −10° C. for 30min. It was transferred into water, neutralized using a saturatedaqueous solution of sodium bicarbonate. The mixture was then extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane)to afford (±)-172.6. MS (ES): m/z 346.24 [M+H]⁺.

Synthesis of compound (±)-172.7. A mixture of compound (±)-172.6 (1.82g, 5.27 mmol, 1.0 equiv), 19.2 (1.15 g, 5.27 mmol, 1.0 equiv) and cesiumcarbonate (5.13 g, 15.81 mmol, 3.0 equiv) in DMF (20 mL) was stirred at120° C. for 5 h. The reaction mixture was transferred into water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 4% ethyl acetate inhexane) to afford (±)-172.7. MS (ES): m/z 413.5 [M+H]⁺.

Synthesis of compound (±)-172.8. A mixture of compound (±)-172.7 (1.0 g,2.42 mmol, 1.0 equiv) and 20% palladium hydroxide (0.500 g) in methanol(20 mL) was stirred under hydrogen (1 atm) for 30 min. The reactionmixture was filtered through a pad of Celite® and washed with 10%methanol in dichloromethane. The filtrate was concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane) to afford(±)-172.8. MS (ES): m/z 323.4 [M+H]⁺.

Synthesis of compound (±)-172.9. To a solution of (±)-172.8 (0.364 g,1.13 mmol, 1.0 equiv) in methanol (7 mL) was added formaldehyde solution(37% in water) (0.5 mL, 5.65 mmol, 5.0 equiv), and the reaction mixturewas stirred at room temperature for 10 min. To the mixture was addedacetic acid (0.169 g, 2.82 mmol, 2.5 equiv) followed by sodiumcyanoborohydride (0.350 g, 5.65 mmol, 5.0 equiv) at 0° C. The reactionmixture was stirred at 0° C. for 15 min. It was poured over ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 20% ethylacetate in hexane) to afford (±)-172.9. MS (ES): m/z 337.5 [M+H]⁺.

Synthesis of compound 172.10 and 172.11. The racemate was prepared from(±)-172.9 following the procedure described in the synthesis of compound120.6. The residue was purified by flash column chromatography on silicagel (CombiFlash®, 40% ethyl acetate in hexane). The enantiomers wereseparated by HPLC (column: CHIRALPAK IB-N (250 mm×21 mm, 5 μm); mobilephase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in 2-propanol; flowrate=18 mL/min) to afford first eluting fraction (172.10) and secondeluting fraction (170.11). MS (ES): m/z 259.3 [M+H]⁺. (*Absolutestereochemistry not determined.)

Synthesis of I-172-a. Compound I-172-a was prepared from compound 172.10and 155.3 following the procedure described in the synthesis of compoundI-169-a. The product was purified by preparative HPLC. MS (ES): m/z:570.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54 (s, 1H), 9.82 (s, 1H),8.19-8.17 (d, J=6.0 Hz, 1H), 7.95 (s, 1H), 7.69-7.68 (d, J=2.0 Hz, 1H),6.67-6.65 (m, 2H), 5.25-5.19 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H),3.61-3.52 (m, 2H), 3.27-3.23 (m, 1H), 2.85-2.79 (m, 1H), 2.40 (s, 3H),2.05 (s, 3H), 1.41 (s, 9H).

Synthesis of I-172-b. Compound I-172-b was prepared from compound 172.10and 155.3 following the procedure described in the synthesis of compoundI-169-a. The product was purified by preparative HPLC. MS (ES): m/z:570.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.55 (s, 1H), 9.83 (s, 1H),8.18-8.16 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.67 (bs, 1H), 6.66-6.64 (m,2H), 5.22-5.18 (m, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.59-3.52 (m, 2H),3.26-3.21 (m, 1H), 2.86-2.78 (m, 1H), 2.39 (s, 3H), 2.03 (s, 3H), 1.40(s, 9H).

Example 173:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 173.2. Compound 173.2 was prepared from compound173.1 following the procedure described in the synthesis of compound28.5. The crude product was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆, 400 MHz): δ 5.24 (bs, 1H), 3.55-3.51 (m,2H), 3.48-3.39 (m, 2H), 3.24 (s, 3H), 2.12 (bs, 2H), 1.41 (s, 9H).

Synthesis of compound 173.3. Compound 173.3 was prepared from compound173.2 and 19.2 following the procedure described in the synthesis ofcompound 28.7. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 10-12% ethyl acetate in hexane). MS (ES):m/z 387.5 [M+H]⁺.

Synthesis of compound 173.4. To a solution of 173.3 (4.1 g, 10.61 mmol,1.0 equiv) in dichloromethane (40 mL) was added trifluoroacetic acid (10mL) at 0° C. The reaction mixture was stirred at room temperature for 3h. It was poured over ice-water, followed by addition of saturatedaqueous sodium bicarbonate solution and product was extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain 173.4. MS (ES): m/z 287.4 [M+H]⁺.

Synthesis of compound 173.5. A mixture of 173.4 (1.0 g, 3.49 mmol, 1.0equiv), 1-bromo-2-methoxyethane (0.582 g, 4.19 mmol, 1.2 equiv),potassium carbonate (1.44 g, 10.47 mmol, 3.0 equiv) and potassium iodide(0.028 g, 0.174 mmol, 0.05 equiv) in DMF (10 mL) was heated at 120° C.for 5 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 6-8% ethyl acetate in hexane) to afford 173.5.MS (ES): m/z 345.5 [M+H]⁺.

Synthesis of compound 173.6. Compound 173.6 was prepared from 173.5following the procedure described in the synthesis of compound 120.6.The product was purified by flash column chromatography on silica gel(CombiFlash®, 4-5% methanol in dichloromethane) to afford 173.6. MS(ES): m/z 223.3 [M+H]⁺.

Synthesis of I-173. A mixture of 169.7 (0.100 g, 0.257 mmol, 1.0 equiv),173.6 (0.082 g, 0.309 mmol, 1.2 equiv) and sodium tert-butoxide (0.049g, 0.514 mmol, 2.0 equiv) in 1,4-dioxane (3 mL) was degassed by bubblingargon through for 10 min. Under argon atmosphere4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.029 g, 0.0514 mmol,0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.0257mmol, 0.1 equiv) were added, again degassed for 5 min. The reactionmixture was stirred at 150° C. in a microwave reactor for 1 h. Thereaction mixture was cooled to room temperature, transferred into waterand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 6-8% methanol indichloromethane) to afford I-173. MS (ES): m/z: 574.5 [M+H]⁺, ¹H NMR(DMSO-d₆, 400 MHz): 10.84 (s, 1H), 9.90 (s, 1H), 8.20-8.19 (d, J=5.6 Hz,1H), 7.96 (bs, 1H), 7.64-7.63 (m, 2H), 6.71-6.69 (m, 1H), 6.58 (s, 1H),5.08-5.04 (m, 1H), 3.68 (s, 3H), 3.47-3.44 (m, 2H), 3.25 (s, 3H),3.12-3.07 (m, 1H), 2.82-2.65 (m, 5H), 2.27-2.25 (m, 1H), 2.20-2.17 (m,1H), 1.98-1.95 (m, 1H), 1.40 (s, 9H), 0.77-0.75 (m, 4H).

Example 174:(R)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-174. Compound I-174 was prepared following the proceduresdescribed in the synthesis of compound I-173. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 6-8% methanolin dichloromethane). MS (ES): m/z: 574.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz): 10.83 (s, 1H), 9.90 (s, 1H), 8.19-8.17 (d, J=5.6 Hz, 1H),7.95-7.94 (d, J=2.0 Hz, 1H), 7.62 (bs, 2H), 6.69-6.68 (m, 1H), 6.56 (s,1H), 5.05-5.03 (m, 1H), 3.66 (s, 3H), 3.45-3.42 (m, 2H), 3.24 (s, 3H),3.10-3.06 (m, 1H), 2.82-2.75 (m, 2H), 2.71-2.55 (m, 3H), 2.27-2.25 (m,1H), 2.20-2.17 (m, 1H), 1.96 (bs, 1H), 1.39 (s, 9H), 0.74 (bs, 4H).

Example 175:(R)—N-(4-((2-((5-(tert-butyl)-1-(2,2-dimethyltetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-(2,2-dimethyltetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-175.2. To a solution of (±)-175.1 (9.5 g,93.06 mmol, 1.0 equiv) and imidazole (14.55 g, 214.03 mmol, 2.3 equiv)in dichloromethane (150 mL) at 0° C. was addedtertbutyldiphenylchlorosilane (31.04 g, 111.67 mmol, 1.2 equiv). Thereaction mixture was allowed to warm to rt and stirred for 2 h. It waspoured over ice-water and was extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 6% ethyl acetate in hexane) to afford (±)-175.2. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.74-7.65 (m, 4H), 7.51-7.39 (m, 6H), 4.61-4.56(m, 1H), 4.28-4.24 (m, 1H), 4.10-4.04 (m, 1H), 2.29-2.14 (m, 2H), 1.03(s, 9H).

Synthesis of compound (±)-175.3. To a solution of (±)-175.2 (28 g, 82.23mmol, 1.0 equiv) in THF (560 mL) at −78° C. was added methyl magnesiumbromide (3.0M in diethyl ether) (164 mL, 493.38 mmol, 6.0 equiv) andstirred for 15 min. It was allowed to warm to rt and stirred at for 1 h.The reaction mixture was transferred into saturated ammonium chlorideand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 50% ethyl acetate inhexane) to afford (±)-175.3. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.67-7.62 (m,4H), 7.47-7.41 (m, 6H), 4.38 (s, 1H), 4.26-4.23 (m, 1H), 3.46-3.43 (m,1H), 3.20-3.15 (m, 1H), 3.06-3.02 (m, 1H), 1.85-1.80 (m, 1H), 1.53-1.48(m, 1H), 1.10-1.09 (d, 6H), 0.98 (s, 9H).

Synthesis of compound (±)-175.4. In a solution of (±)-175.3 (22 g, 59.05mmol, 1.0 equiv) in pyridine (220 mL) was added p-toluenesulfonylchloride (22.43 g, 118.1 mmol, 2.0 equiv) in portions at 0° C. It wasstirred at rt for 2 h and heated to reflux for 2 h. The reaction mixturewas cooled to rt and poured into water. It was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane)to afford (±)-175.4. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.63-7.61 (m, 4H),7.51-7.43 (m, 6H), 3.98-3.95 (m, 1H), 3.77-3.71 (m, 1H), 3.59-3.53 (m,1H), 1.94-1.83 (m, 1H), 1.74-1.69 (m, 1H), 1.14 (s, 3H), 1.05 (s, 9H),0.94 (s, 3H).

Synthesis of compound (±)-175.5. To a solution of (±)-175.4 (17 g, 47.95mmol, 1.0 equiv) in THF (200 mL) was added tetra-N-butyl ammoniumfluoride (1M in THF) (96 mL, 95.9 mmol, 2.0 equiv) at 0° C. and stir for30 min. The reaction mixture was stirred for 6 h. It was poured overcrushed ice, stirred, neutralized with saturated aqueous solution ofsodium bicarbonate and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,50% ethyl acetate in hexane) to afford (±)-175.5. ¹H NMR (DMSO-d₆, 400MHz): δ 4.83-4.82 (d, 1H), 3.77-3.72 (m, 2H), 3.66-3.61 (m, 1H),2.18-2.10 (m, 1H), 1.76-1.69 (m, 1H), 1.06 (s, 6H).

Synthesis of compound 175.6. To a solution of (±)-175.5 (4.0 g, 34.44mmol, 1.0 equiv) in dichloromethane (5 mL) was added pyridiniumchlorochromate (22.21, 103.32 mmol, 3.0 equiv) at 0° C. The reactionmixture was stirred at room temperature for 12 h. After completion ofreaction, diethyl ether was added and precipitated solids were removedby filtration through a pad of Celite®. The filtrate was concentratedunder reduced pressure to afford 175.6, which was used in the next stepwithout further purification.

Synthesis of compound 175.7. To a solution of 175.6 (3.9 g, 34.17 mmol,1.0 equiv) in ethanol (40 mL) was added tert-butyl hydrazine carboxylate(4.96 g, 37.58 mmol, 1.1 equiv). The reaction mixture was heated toreflux for 12 h and cooled to rt. Solvent was removed under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 20% ethyl acetate in hexane) to afford 175.7.¹H NMR (DMSO-d₆, 400 MHz): δ 9.51 (s, 1H), 3.90-3.87 (m, 2H), 2.60-2.57(m, 2H), 1.43 (s, 9H), 1.21 (s, 6H).

Synthesis of compound (±)-175.8. To a solution of 175.7 (3.0 g, 13.14mmol, 1.0 equiv) in acetic acid (30 mL) was added sodiumcyanoborohydride (0.814 g, 13.14 mmol, 1.0 equiv) in portions. Thereaction mixture was stirred at room temperature for 3 h. It was pouredover ice-water, stirred, neutralized with 1 N sodium hydroxide solutionand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to obtain (±)-175.8. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.27 (s, 1H), 4.45 (s, 1H), 3.69-3.61 (m, 2H),3.12 (bs, 1H), 2.02-1.98 (m, 1H), 1.73-1.68 (m, 1H), 1.39 (s, 9H), 1.05(s, 6H).

Synthesis of compound (±)-175.9. To a solution of (±)-175.8 (2.5 g,10.86 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) was added hydrogenchloride (4M in dioxane, 27 mL, 108.6 mmol, 10 equiv) at 0° C. Thereaction mixture was stirred at room temperature for 12 h. It wasconcentrated under reduced pressure to obtain (±)-175.9. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.85 (bs, 1H), 3.80-3.76 (m, 1H), 3.71-3.65 (m,2H), 3.57 (s, 2H), 3.21 (bs, 1H), 2.25-2.20 (m, 1H), 1.91 (bs, 1H), 1.19(s, 3H), 1.08 (s, 3H).

Synthesis of compound (±)-175.11. To a solution of (±)-175.9 (1.8 g,10.80 mmol, 1.0 equiv) in ethanol (20 mL) was added ethyl5,5-dimethyl-2,4-dioxohexanoate (175.10, 2.16 g, 10.80 mmol, 1.0 equiv).The reaction mixture was heated to reflux for 12 h. It was concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 25% ethyl acetate in hexane)to afford (±)-175.11. MS (ES): m/z 295.4 [M+H]⁺.

Synthesis of compound (±)-175.12. To a solution of (±)-175.11 (1.8 g,6.11 mmol, 1.0 equiv) in ethanol:water (8:2, 20 mL) was added powderedsodium hydroxide (0.977 g, 24.44 mmol, 4.0 equiv) at 0° C. The reactionmixture was allowed to warm to rt and stirred for 12 h. It was pouredover ice-water, stirred and adjusted pH to 2 with 1N HCl solution. Themixture was extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure which was triturated withdiethyl ether to obtain (±)-175.12. MS (ES): m/z 267.3 [M+H]⁺.

Synthesis of compound (±)-175.13. To a solution of (±)-175.12 (0.5 g,1.88 mmol, 1.0 equiv) in tert-butanol (5 mL) was added triethylamine(0.52 mL, 3.76 mmol, 2.0 equiv) followed by diphenylphosphoryl azide(0.775 g, 2.82 mmol, 1.5 equiv). The reaction mixture was stirred at 90°C. for 12 h. It was poured over ice-water, stirred and extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford (±)-175.13. MS (ES): m/z 501.6 [M+H]⁺.

Synthesis of compound (±)-175.14. To a solution of (±)-175.13 (0.5 g,0.998 mmol, 1.0 equiv) in ethanol:water (5:1, 10 mL) was added potassiumhydroxide (20% in water 2.0 mL). The reaction mixture was stirred at160° C. in a microwave reactor for 1 h. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 1.8% methanol indichloromethane) to afford (±)-175.14. MS (ES): m/z 238.4 [M+H]⁺.

Synthesis of compound I-175-a and I-175-b. Compound (±)-I-175 wasprepared from compound (±)-175.14 and 96.7 following the proceduredescribed in the synthesis of compound I-108. The product was purifiedby flash column chromatography on C-18 silica gel (CombiFlash®, 86%acetonitrile in water). The enantiomers were separated by SFC (column:CHIRAL-cel OX-H (250 mm×21 mm, 5 μm); mobile phase: (A) liquid carbondioxide, (B) 0.1% DEA in MeOH:acetonitrile (50:50); flow rate=80 mL/min)to afford first eluting fraction (I-175-a) and second eluting fraction(I-175-b). (*Absolute stereochemistry not determined.)

I-175-a: MS (ES): m/z: 519.4 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.82 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.65-7.63 (m, 2H),6.65 (s, 1H), 6.60 (s, 1H), 4.79-4.77 (m, 1H), 4.23-4.21 (m, 1H),3.84-3.82 (m, 1H), 3.67 (s, 3H), 2.33-2.28 (m, 2H), 2.03 (s, 3H), 1.40(s, 9H), 1.27 (s, 3H), 0.94 (s, 3H).

I-175-b: MS (ES): m/z: 519.9 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.82 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.66-7.64 (m, 2H),6.65 (s, 1H), 6.61 (s, 1H), 4.80-4.78 (m, 1H), 4.23-4.22 (m, 1H),3.85-3.83 (m, 1H), 3.68 (s, 3H), 2.34-2.28 (m, 2H), 2.04 (s, 3H), 1.41(s, 9H), 1.28 (s, 3H), 0.90 (s, 3H).

Example 176:(S)—N-(4-((2-((5-(tert-butyl)-1-(2-hydroxypropyl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamideand(R)—N-(4-((2-((5-(tert-butyl)-1-(2-hydroxypropyl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound (±)-176.2. To a suspension of sodium hydride (2.88g, 72.04 mmol, 1.5 equiv) in THF (25 mL) was added solution of methyl2-hydroxypropanoate ((±)-176.1, 5.0 g, 48.03 mmol, 1.0 equiv) in THF (25mL) at 0° C. and stirred for 1 h. To the reaction mixture was addedbenzyl bromide (6.85 mL, 57.63 mmol, 1.2 equiv) and stirred at roomtemperature for 2 h. It was poured over crashed ice, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2% ethyl acetate inhexane) to afford (±)-176.2. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.39-7.30 (m,5H), 4.59-4.56 (d, 1H), 4.46-4.43 (d, 1H), 4.16-4.11 (q, 1H), 3.69 (s,3H), 1.34 (s, 3H).

Synthesis of compound (±)-176.3. To a solution of (±)-176.2 (3.0 g,15.45 mmol, 1.0 equiv) in THF (30 mL), was added lithium aluminumhydride solution (1 M in THF) (39 mL, 38.62 mmol, 2.5 equiv) at 0° C.and stirred for 1 h. The reaction was quenched by saturated aqueoussolution of sodium sulfate. Precipitated solids were removed byfiltration through a pad of Celite® and washed with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford (±)-176.3. ¹H NMR(DMSO-d₆, 400 MHz): δ 7.35-7.25 (m, 5H), 4.65-4.62 (t, 1H), 4.50 (s,2H), 3.52-3.42 (m, 2H), 3.33 (bs, 1H), 1.10 (s, 3H).

Synthesis of compound (±)-176.4. To a solution of (±)-176.3 (2.5 g,15.04 mmol, 1.0 equiv) and triethylamine (6.3 mL, 45.12 mmol, 3.0 equiv)in dichloromethane (25 mL) at 0° C. was added MSCl (2.3 mL, 30.08 mmol,2.0 equiv). The reaction mixture was stirred at 0° C. for 30 min. It waspoured over ice-water, stirred and extracted with dichloromethane. Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate followed by brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford (±)-176.4.

Synthesis of compound (±)-176.5. Compound (±)-176.5 was prepared fromcompound (±)-176.4 and 19.2 following the procedure described in thesynthesis of compound 28.7. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 1-2% ethyl acetate inhexane). MS (ES): m/z 366.45 [M+H]⁺.

Synthesis of compound 176.6 and 176.7. The racemate was prepared from(±)-176.5 following the procedure described in the synthesis of compound120.6. The product was purified by flash column chromatography on silicagel (CombiFlash®, 25% ethyl acetate in hexane). The enantiomers wereseparated by HPLC (column: CHIRALPAK IG (250 mm×21 mm, 5 μm); mobilephase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA in 2-propanol; flowrate=20 mL/min) to afford first eluting fraction (176.6) and secondeluting fraction (176.7). MS (ES): m/z 288.4 [M+H]⁺. (*Absolutestereochemistry not determined.)

Synthesis of compound 176.8. Compound 176.8 was prepared from compound176.6 and 170.1 following the procedure described in the synthesis ofcompound I-169-a. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5% methanol indichloromethane). MS (ES): m/z: 625.5 [M+H]⁺. (*Absolute stereochemistrynot determined.)

Synthesis of I-176-a. To a solution of 176.8 (0.065 g, 0.104 mmol, 1.0equiv) in dichloromethane (2 mL) was added triflic acid (0.1 mL) at 0°C. and stirred for 5 min. The reaction mixture was transferred intoice-saturated aqueous sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC to affordI-176-a. MS (ES): m/z: 535.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.85(s, 1H), 9.77 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.92 (s, 1H),7.65-7.64 (d, J=2.4 Hz, 1H), 6.69-6.68 (m, 1H), 6.55 (s, 1H), 4.98-4.97(d, 1H), 4.25-4.22 (m, 1H), 4.06-4.04 (m, 1H), 3.96-3.92 (m, 1H), 3.89(s, 3H), 3.81 (s, 3H), 1.96 (bs, 1H), 1.39 (s, 9H), 1.14-1.13 (m, 3H),0.76-0.74 (d, 4H). (*Absolute stereochemistry not determined.)

Synthesis of compound 176.9. Compound 176.9 was prepared from compound176.7 and 170.1 following the procedure described in the synthesis ofcompound I-169-a. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 2.5% methanol indichloromethane). MS (ES): m/z: 625.5 [M+H]⁺. (*Absolute stereochemistrynot determined.)

Synthesis of I-176-b. Compound I-176-b was prepared from compound 176.9following the procedure described in the synthesis of compound I-176-a.The product was purified by preparative HPLC. MS (ES): m/z: 535.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.85 (s, 1H), 9.76 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.67-7.66 (d, J=2.4 Hz, 1H),6.70-6.68 (m, 1H), 6.56 (s, 1H), 4.98-4.97 (d, 1H), 4.25-4.22 (m, 1H),4.10-4.05 (m, 1H), 3.98-3.93 (m, 1H), 3.91 (s, 3H), 3.82 (s, 3H),1.99-1.96 (m, 1H), 1.40 (s, 9H), 1.16-1.14 (m, 3H), 0.77-0.76 (d, 4H).(*Absolute stereochemistry not determined.)

Example 177:(R)—N-(4-((7-methoxy-1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-177. Compound I-177 was prepared from compound 126.7 and170.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3% methanol in dichloromethane). MS (ES): m/z: 609.46[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.87 (s, 1H), 10.43 (s, 1H),8.21-8.19 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.66 (s, 1H), 7.37 (s, 1H),6.71-6.69 (m, 1H), 5.16 (bs, 1H), 4.12-4.06 (m, 2H), 3.92 (s, 4H), 3.86(s, 3H), 2.68 (bs, 1H), 2.34 (bs, 1H), 1.97 (bs, 1H), 1.24 (bs, 1H),0.75 (bs, 4H).

Example 178:(S)—N-(4-((7-methoxy-1-methyl-2-((5-(perfluoroethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-178. Compound I-178 was prepared from compound 127.3 and170.1 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3% methanol in dichloromethane). MS (ES): m/z: 609.48[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.87 (s, 1H), 10.44 (s, 1H),8.21-8.20 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.67-7.66 (d, J=2.0 Hz, 1H),7.37 (s, 1H), 6.71-6.69 (m, 1H), 5.17 (bs, 1H), 4.14-4.06 (m, 2H), 3.93(s, 4H), 3.83 (s, 3H), 2.68 (bs, 1H), 2.34 (bs, 1H), 2.00-1.94 (m, 1H),1.25 (bs, 1H), 0.77-0.76 (m, 4H).

Example 179:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 179.1. To a solution of 173.4 (2.0 g, 6.98 mmol,1.0 equiv) and 1-fluoro-2-iodoethane (1.82 g, 10.47 mmol, 1.5 equiv) inDMF (20 mL) was added potassium carbonate (2.89 g, 20.94 mmol, 3.0equiv) and reaction mixture was stirred at 120° C. for 5 h. It waspoured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4-6% ethyl acetate in hexane) to afford 179.1. MS (ES):m/z 333.4 [M+H]⁺.

Synthesis of compound 179.2. Compound 179.2 was prepared from 179.1following the procedure described in the synthesis of compound 120.6.The product was purified by flash column chromatography on silica gel(CombiFlash®, 4-5% methanol in dichloromethane). MS (ES): m/z 255.3[M+H]⁺.

Synthesis of I-179. Compound I-179 was prepared from compound 179.2 and169.7 following the procedure described in the synthesis of compoundI-169-a. The product was purified by flash column chromatography onsilica gel (CombiFlash®, 3-4% methanol in dichloromethane). MS (ES):m/z: 562.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.84 (s, 1H), 9.91 (s,1H), 8.20-8.18 (d, J=6.0 Hz, 1H), 7.96 (bs, 1H), 7.64-7.63 (m, 2H),6.71-6.69 (m, 1H), 6.58 (s, 1H), 5.11-5.07 (m, 1H), 4.63-4.60 (m, 1H),4.51-4.48 (m, 1H), 3.67 (s, 3H), 3.15-3.11 (t, 2H), 2.87-2.82 (m, 2H),2.78-2.75 (m, 2H), 2.34 (bs, 1H), 2.29-2.21 (m, 1H), 1.98-1.95 (m, 1H),1.40 (s, 9H), 0.77-0.75 (m, 4H).

Example 180:(R)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-180. Compound I-180 was prepared following the proceduresdescribed in the synthesis of compound I-179. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 3-4% methanolin dichloromethane). MS (ES): m/z: 562.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz): 10.83 (s, 1H), 9.90 (s, 1H), 8.20-8.18 (d, J=6.0 Hz, 1H), 7.96(bs, 1H), 7.64 (bs, 2H), 6.71-6.69 (m, 1H), 6.58 (s, 1H), 5.11-5.07 (m,1H), 4.63-4.60 (m, 1H), 4.51-4.48 (m, 1H), 3.67 (s, 3H), 3.15-3.11 (t,2H), 2.86-2.83 (m, 2H), 2.78-2.75 (m, 2H), 2.34 (bs, 1H), 2.21-2.20 (m,1H), 1.98-1.97 (m, 1H), 1.40 (s, 9H), 0.76-0.75 (m, 4H).

Example 181:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 181.1. A mixture of 14.5 (0.433 g, 2.43 mmol, 1.0equiv), 141.3 (0.500 g, 2.43 mmol, 1.0 equiv) and potassium carbonate(0.838 g, 6.07 mmol, 2.5 equiv) in DMF (5 mL) was stirred at 80° C. for2 h. The reaction mixture was cooled to room temperature, transferredinto ice-water and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 2.7%methanol in dichloromethane) to afford 181.1. MS (ES): m/z 364.3 [M+H]⁺.

Synthesis of compound 181.2. To a solution of 181.1 (0.590 g, 1.62 mmol,1.0 equiv) in ethanol:water (2:1, 10 mL) was added iron powder (0.445 g,8.1 mmol, 5 equiv) followed by ammonium chloride (0.445 g, 8.1 mmol, 5equiv). The reaction mixture was stirred at 80° C. for 1 h. It waspoured over ice-water, filtered and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3.3% methanol in dichloromethane) to afford 181.2. MS(ES): m/z 334.7 [M+H]⁺.

Synthesis of compound 181.3. Compound 181.3 was prepared from compound181.2 following the procedure described in the synthesis of compound148.8. The product was triturated with hexane to afford 181.3. MS (ES):m/z: 376.7 [M+H]⁺.

Synthesis of compound 181.4. Compound 181.4 was prepared from compound181.3 following the procedure described in the synthesis of compound148.9. The residue was purified by flash column chromatography on silicagel (CombiFlash®, 3.0% methanol in dichloromethane). MS (ES): m/z 423.7[M+H]⁺.

Synthesis of I-184. Compound I-184 was prepared from compound 181.4 and173.6 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 6-8% methanol in dichloromethane). MS (ES): m/z: 608.4[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.86 (s, 1H), 9.85 (s, 1H),8.21-8.19 (d, J=5.6 Hz, 1H), 8.06 (s, 1H), 7.63-7.62 (d, J=1.6 Hz, 1H),6.70-6.69 (d, J=3.6 Hz, 1H), 6.52 (s, 1H), 5.08-5.04 (m, 1H), 3.93 (s,3H), 3.47-3.44 (m, 2H), 3.26 (s, 3H), 3.11-3.07 (m, 1H), 2.81-2.77 (m,2H), 2.74-2.67 (m, 2H), 2.27-2.11 (m, 2H), 1.99-1.96 (m, 2H), 1.40 (s,9H), 0.78-0.76 (m, 4H).

Example 182:(R)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-methoxyethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-182. Compound I-182 was prepared from compound 181.4 and174.6 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 6-8% methanol in dichloromethane). MS (ES): m/z: 608.7[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.85 (s, 1H), 9.83 (s, 1H),8.21-8.19 (d, J=5.6 Hz, 1H), 8.05 (s, 1H), 7.63-7.62 (d, J=2.4 Hz, 1H),6.70-6.68 (m, 1H), 6.52 (s, 1H), 5.08-5.04 (m, 1H), 3.93 (s, 3H),3.47-3.44 (m, 2H), 3.26 (s, 3H), 3.11-3.07 (m, 1H), 2.81-2.77 (m, 2H),2.74-2.67 (m, 2H), 2.27-2.11 (m, 2H), 1.99-1.96 (m, 2H), 1.40 (s, 9H),0.78-0.76 (m, 4H).

Example 183:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-183. A mixture of 170.1 (0.070 g, 0.187 mmol, 1.0 equiv),179.2 (0.052 g, 0.205 mmol, 1.1 equiv), tripotassium phosphate (0.119 g,0.561 mmol, 3.0 equiv) and DMF (3 mL) was degassed by bubbling argonthrough for 10 min. Under argon atmosphere[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (0.044 g, 0.0561 mmol, 0.3 equiv) wasadded, again degassed for 5 min. The reaction mixture was stirred atroom temperature for 3 h. It was transferred into water and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC. MS (ES):m/z: 592.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.86 (s, 1H), 9.81 (s,1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.91 (s, 1H), 7.65 (bs, 1H), 6.70-6.68(m, 1H), 6.52 (s, 1H), 5.09-5.06 (m, 1H), 4.61-4.59 (m, 1H), 4.49-4.47(m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.17-3.09 (m, 1H), 2.85-2.73 (m,5H), 2.28-2.18 (m, 2H), 1.98-1.95 (m, 1H), 1.39 (s, 9H), 0.76-0.75 (m,4H).

Example 184:(R)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-184. Compound I-184 was prepared from compound 170.1 and180.2 following the procedure described in the synthesis of compoundI-183. The product was purified by preparative HPLC. MS (ES): m/z: 592.7[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): 10.86 (s, 1H), 9.82 (s, 1H),8.19-8.18 (d, J=5.6 Hz, 1H), 7.91 (s, 1H), 7.65 (bs, 1H), 6.70-6.68 (m,1H), 6.52 (s, 1H), 5.09-5.06 (m, 1H), 4.61-4.59 (m, 1H), 4.49-4.47 (m,1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.17-3.09 (m, 1H), 2.85-2.67 (m, 5H),2.28-2.18 (m, 2H), 1.98-1.95 (m, 1H), 1.39 (s, 9H), 0.76-0.75 (m, 4H).

Example 185:(S)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-185. Compound I-185 was prepared from compound 142.2 and179.2 following the procedure described in the synthesis of compoundI-183. The product was purified by preparative HPLC. MS (ES): m/z: 570.4[M+H]⁺, LCMS purity: 100%, HPLC purity: 95.06%, Chiral HPLC purity:97.51%, ¹H NMR (DMSO-d₆, 400 MHz): 10.57 (s, 1H), 10.04 (s, 1H),8.18-8.16 (d, J=5.6 Hz, 1H), 8.07 (s, 1H), 7.63 (bs, 1H), 6.51-6.63 (m,1H), 6.52 (s, 1H), 5.10-5.06 (m, 1H), 4.61-4.58 (m, 1H), 4.49-4.46 (m,1H), 3.92 (s, 3H), 3.17-3.09 (m, 2H), 2.85-2.73 (m, 5H), 2.21-2.19 (m,1H), 2.03 (s, 3H), 1.38 (s, 9H).

Example 186:(R)—N-(4-((2-((5-(tert-butyl)-1-(1-(2-fluoroethyl)pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-186. Compound I-186 was prepared from compound 142.2 and180.2 following the procedure described in the synthesis of compoundI-183. The product was purified by preparative HPLC. MS (ES): m/z: 570.5[M+H]⁺, LCMS purity: 100%, HPLC purity: 97%, Chiral HPLC purity: 98.71%,¹H NMR (DMSO-d₆, 400 MHz): 10.54 (s, 1H), 10.02 (s, 1H), 8.20-8.19 (d,J=5.6 Hz, 1H), 8.09 (s, 1H), 7.65 (bs, 1H), 6.66-6.64 (m, 1H), 6.54 (s,1H), 5.12-5.10 (m, 1H), 4.63-4.60 (m, 1H), 4.51-4.48 (m, 1H), 3.94 (s,3H), 3.16-3.11 (m, 2H), 2.86-2.68 (m, 5H), 2.22-2.20 (m, 1H), 2.05 (s,3H), 1.38 (s, 9H).

Example 187:(S)—N-(4-((2-((5-(tert-butyl)-4-(tetrahydrofuran-3-yl)thiazol-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(R)—N-(4-((2-((5-(tert-butyl)-4-(tetrahydrofuran-3-yl)thiazol-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 187.2. A solution of 187.1 (2.0 g, 12.80 mmol, 1.0equiv), phthalic anhydride (3.79 g, 25.60 mmol, 2.0 equiv) andtriethylamine (5.4 mL, 38.4 mmol, 3.0 equiv) in toluene (20 mL) wasstirred at 200° C. in a microwave reaction for 2 h. The reaction mixturewas transferred into water, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 11% ethyl acetate in hexane) to afford 187.2. MS (ES): m/z287.3 [M+H]⁺.

Synthesis of compound 187.3. To a solution of 187.2 (2.1 g, 7.33 mmol,1.0 equiv) in DMF (20 mL) was added N-bromosuccinimide (6.5 g, 36.6mmol, 5.0 equiv). The reaction mixture was stirred at room temperaturefor 3 h. The reaction mixture was transferred into water, stirred andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 15% ethyl acetate inhexane) to afford 187.3. MS (ES): m/z 366.2 [M+H]⁺.

Synthesis of compound 187.4. To a solution of 187.3 (1.9 g, 5.2 mmol,1.0 equiv) in ethanol (20 mL) was added hydrazine (0.34 mL, 10.4 mmol,2.0 equiv) at 0° C. The reaction mixture was stirred at room temperaturefor 12 h. It was poured over ice-water, stirred and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 70% ethyl acetate in hexane) to afford 187.4.MS (ES): m/z 236.1 [M+H]⁺.

Synthesis of compound 187.6. To a solution of 187.4 (1.0 g, 4.25 mmol,1.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was added 187.5 (2.5g, 12.76 mmol, 3.0 equiv) and potassium carbonate (1.76 g, 12.76 mmol,3.0 equiv). The reaction mixture was degassed by bubbling argon throughfor 10 min. Under argon atmosphere[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex (0.173 g, 0.212 mmol, 0.05 equiv) was added, again degassed for5 min. The reaction mixture was stirred at 130° C. for 3 h. The reactionmixture was cooled to room temperature, filtered through a pad ofCelite®. The filtrate was transferred into water, extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 1% methanol in dichloromethane) to afford187.6. MS (ES): m/z 225.3 [M+H]⁺.

Synthesis of compound (±)-187.7. A mixture of Raney nickel (0.2 g) andcompound 187.6 (0.250 g, 1.11 mmol, 1.0 equiv) in methanol (10 mL) wasstirred under hydrogen atmosphere (1 atm) for 12 h. The reaction mixturewas filtered through a pad of Celite® and washed with methanol. Thefiltrate was concentrated under reduced pressure to afford (±)-187.7. MS(ES): m/z 227.3 [M+H]⁺.

Synthesis of compound I-187-a and I-187-b. Compound (±)-I-187 wasprepared from compound (±)-187.7 and 96.7 following the proceduredescribed in the synthesis of compound I-108. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 2.5% methanolin dichloromethane). The enantiomers were separated by HPLC (column:CHIRALPAK IC (250 mm×21 mm, 5 μm); mobile phase: (A) 0.1% DEA inn-hexane, (B) 0.1% DEA in propane-2-ol:acetonitrile (70:30); flowrate=20 mL/min) to afford first eluting fraction (I-187-a) and secondeluting fraction (I-187-b). (*Absolute stereochemistry not determined.)

I-187-a. MS (ES): m/z: 508.4 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 12.18(s, 1H), 10.53 (s, 1H), 8.18-8.16 (d, J=5.6 Hz, 1H), 8.00 (bs, 1H), 7.67(bs, 2H), 6.67-6.65 (m, 1H), 3.99-3.95 (m, 2H), 3.88-3.82 (m, 1H),3.74-3.51 (m, 5H), 2.18-2.15 (m, 2H), 2.03 (s, 3H), 1.42 (s, 9H).

I-187-b. MS (ES): m/z: 508.4 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 12.19(s, 1H), 10.53 (s, 1H), 8.18-8.16 (d, J=5.6 Hz, 1H), 8.00 (bs, 1H), 7.67(bs, 2H), 6.67-6.65 (m, 1H), 3.99-3.95 (m, 2H), 3.87-3.81 (m, 1H),3.74-3.51 (m, 5H), 2.18-2.15 (m, 2H), 2.03 (s, 3H), 1.42 (s, 9H).

Example 188:N-(4-((2-((5-(tert-butyl)-1-(2,2-difluoroethyl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-188. Compound I-188 was prepared from compound 155.3 and132.2 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 4.5% methanol in dichloromethane). MS (ES): m/z: 515.4[M+H]⁺, LCMS purity: 100%, HPLC purity: 98.79%, ¹H NMR (DMSO-d₆, 400MHz): δ 10.55 (s, 1H), 9.90 (s, 1H), 8.51 (bs, 2H), 8.18-8.16 (d, J=5.6Hz, 1H), 7.94 (s, 1H), 6.66-6.64 (m, 1H), 6.58-6.30 (m, 1H), 4.60-4.59(m, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 2.03 (s, 3H), 1.39 (s, 9H).

Example 189:(R)—N-(4-((2-((5-(tert-butyl)-1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-189.1. To a solution of (±)-175.2 (40 g,117.48 mmol, 1.0 equiv) in THF (120 mL) and diethyl ether (120 mL) at15° C. was added titanium isopropoxide (16.69 g, 58.74 mmol, 0.5 equiv)followed ethyl magnesium bromide (3.0M in diethyl ether) (117.5 mL,352.4 mmol, 3.0 equiv). The reaction mixture was stirred for 1 h. It wastransferred into saturated ammonium chloride and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 40% ethyl acetate in hexane) to afford(±)-189.1. ¹H NMR (CDCl₃, 400 MHz): δ 7.73-7.67 (m, 4H), 7.47-7.39 (m,6H), 3.93-3.88 (m, 1H), 3.67-3.61 (m, 1H), 3.51 (s, 2H), 3.35-3.32 (m,1H), 1.93-1.87 (m, 2H), 1.11 (s, 9H), 0.82-0.76 (m, 1H), 0.61-0.56 (m,1H), 0.40-0.34 (m, 1H), 0.18-0.17 (m, 1H).

Synthesis of compound (±)-189.2. Compound (±)-189.2 was prepared fromcompound (±)-189.1 following the procedure described in the synthesis ofcompound (±)-175.4. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 5% ethyl acetate in hexane)to afford (±)-189.2. ¹H NMR (CDCl₃, 400 MHz): δ 7.67-7.64 (m, 4H),7.47-7.38 (m, 6H), 4.19-4.16 (m, 1H), 4.07-4.01 (m, 1H), 3.82-3.77 (m,1H), 2.15-2.08 (m, 1H), 2.06-1.95 (m, 1H), 1.08 (s, 9H), 0.79-0.66 (m,3H), 0.31-0.22 (m, 1H).

Synthesis of compound (±)-189.3. Compound (±)-189.3 was prepared fromcompound (±)-189.2 following the procedure described in the synthesis ofcompound (±)-175.5. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 50% ethyl acetate in hexane)to afford (±)-189.3. ¹H NMR (CDCl₃, 400 MHz): δ 4.12-3.99 (m, 1H),3.98-3.90 (m, 2H), 2.45-2.36 (m, 1H), 2.12-2.05 (m, 1H), 1.09-0.94 (m,1H), 0.88-0.80 (m, 2H), 0.65-0.59 (m, 1H).

Synthesis of compound 189.4. Compound 189.4 was prepared from compound(±)-189.3 following the procedure described in the synthesis of compound175.6. The crude product was used in the next step without purification.

Synthesis of compound 189.5. Compound 189.5 was prepared from compound189.4 following the procedure described in the synthesis of compound175.7. The product was purified by flash column chromatography on silicagel (CombiFlash®, 17% ethyl acetate in hexane) to afford 189.5. ¹H NMR(DMSO-d₆, 400 MHz): δ 9.60 (s, 1H), 3.98-3.95 (m, 2H), 2.73-2.70 (m,2H), 1.43 (s, 9H), 1.02-0.99 (m, 2H), 0.84-0.81 (m, 2H).

Synthesis of compound (±)-189.6. Compound (±)-189.6 was prepared fromcompound 189.5 following the procedure described in the synthesis ofcompound (±)-175.8. The crude product was used in the next step withoutpurification. ¹H NMR (CDCl₃, 400 MHz): δ 6.59 (s, 1H), 5.33 (s, 1H),4.18-4.07 (m, 2H), 3.93-3.90 (m, 1H), 3.44 (bs, 1H), 2.34-2.31 (m, 1H),1.50 (s, 9H), 1.09-1.06 (m, 2H), 0.75-0.73 (m, 1H), 0.56 (bs, 1H).

Synthesis of compound (±)-189.7. Compound (±)-189.7 was prepared fromcompound (±)-189.6 following the procedure described in the synthesis ofcompound (±)-175.9. The crude product was used in the next step withoutpurification. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.12 (bs, 1H), 3.92-3.90 (m,2H), 3.75-3.70 (m, 2H), 2.29 (bs, 4H), 0.66-0.54 (m, 4H).

Synthesis of compound (±)-189.8. Compound (±)-189.8 was prepared fromcompound (±)-189.7 following the procedure described in the synthesis ofcompound (±)-175.11. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 20% ethyl acetate in hexane)to afford (±)-189.8. MS(ES): m/z 293.4 [M+H]⁺.

Synthesis of compound (±)-189.9. Compound (±)-189.9 was prepared fromcompound (±)-189.8 following the procedure described in the synthesis ofcompound (±)-175.12. The crude product was triturated with diethyl etherto obtain (±)-189.9. MS(ES): m/z 265.3 [M+H]⁺.

Synthesis of compound (±)-189.10. Compound (±)-189.10 was prepared fromcompound (±)-189.9 following the procedure described in the synthesis ofcompound (±)-175.13. The crude product was used in the next step withoutpurification. MS(ES): m/z 497.6 [M+H]⁺.

Synthesis of compound (±)-189.11. Compound (±)-189.11 was prepared fromcompound (±)-189.10 following the procedure described in the synthesisof compound (±)-175.14. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 1.5% methanol indichloromethane) to afford (±)-189.11. MS(ES): m/z 236.4 [M+H]⁺.

Synthesis of compound I-189-a and I-189-b. Compound (±)-I-189 wasprepared from compound (±)-189.11 and 148.9 following the proceduredescribed in the synthesis of compound I-108. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 1.8% methanolin dichloromethane). The enantiomers were separated by HPLC (column:CHIRALPAK IB-N (250 mm×21 mm, 5 μm); mobile phase: (A) 0.3% DEA inn-hexane, (B) 0.3% DEA in propane-2-ol; flow rate=20 mL/min) to affordfirst eluting fraction (I-189-a) and second eluting fraction (I-189-b).(*Absolute stereochemistry not determined.)

I-189-a: MS(ES): m/z: 517.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.53(s, 1H), 9.96 (s, 1H), 8.18-8.16 (d, J=5.6 Hz, 1H), 7.96 (s, 1H),7.66-7.63 (m, 2H), 6.66-6.64 (m, 1H), 6.58 (s, 1H), 5.03-5.00 (m, 1H),4.24-4.19 (m, 1H), 3.85-3.79 (m, 1H), 3.68 (s, 3H), 2.67-2.61 (m, 1H),2.37-2.33 (m, 1H), 2.03 (s, 3H), 1.34 (s, 9H), 0.91-0.85 (m, 2H),0.80-0.75 (m, 2H).

I-189-b: MS(ES): m/z: 517.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.54(s, 1H), 9.97 (s, 1H), 8.18-8.16 (d, J=5.6 Hz, 1H), 7.96 (s, 1H),7.66-7.63 (m, 2H), 6.66-6.64 (m, 1H), 6.58 (s, 1H), 5.03-5.00 (m, 1H),4.24-4.19 (m, 1H), 3.85-3.79 (m, 1H), 3.68 (s, 3H), 2.67-2.63 (m, 1H),2.39-2.33 (m, 1H), 2.03 (s, 3H), 1.34 (s, 9H), 0.91-0.86 (m, 2H),0.80-0.75 (m, 2H).

Example 190:(R)—N-(4-((2-((5-(tert-butyl)-1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-1-(4-oxaspiro[2.4]heptan-7-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-I-190. Compound (±)-I-190 was prepared fromcompound (±)-189.11 and 155.3 following the procedure described in thesynthesis of Compound I-108. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 3.5% methanol in DCM).MS(ES): m/z: 547.5 [M+H]⁺.

Synthesis of compounds I-190-a and I-190-b. The enantiomers of (±)-I-190were separated by HPLC (column CHIRALPAK IB-N (250 mm×21 mm, 5 μm);mobile phase: (A) 0.1% diethylamine in n-hexane, (B) 0.1% diethylaminein isopropanol:methanol (50:50); flow rate=20 mL/min) to afford firsteluting fraction (I-190-a) and second eluting fraction (I-190-b).(*Absolute stereochemistry not determined.)

I-190-a: MS(ES): m/z: 547.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56(s, 1H), 9.87 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.69(s, 1H), 6.66-6.65 (d, J=3.6 Hz, 1H), 6.54 (s, 1H), 5.03-5.00 (m, 1H),4.23-4.22 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.55-3.52 (m, 1H), 2.05(s, 3H), 1.34 (s, 9H), 1.25 (s, 2H), 0.90-0.88 (m, 2H), 0.81-0.76 (m,2H).

I-190-b: MS(ES): m/z: 547.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.56(s, 1H), 9.87 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.69(s, 1H), 6.66-6.65 (d, J=3.6 Hz, 1H), 6.54 (s, 1H), 5.04-5.02 (m, 1H),4.23-4.22 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.55-3.52 (m, 1H), 2.05(s, 3H), 1.34 (s, 9H), 1.25 (s, 2H), 0.90-0.88 (m, 2H), 0.81-0.76 (m,2H).

Example 191:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound I-191. Compound I-191 was prepared from compounds170.1 and 61.4 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.1% methanol in DCM). MS(ES): m/z: 502.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.87 (s, 1H), 8.34 (s, 1H),8.31-8.30 (d, J=2.0 Hz, 1H), 8.20-8.19 (d, J=5.6 Hz, 1H), 8.02 (s, 1H),7.67-7.66 (d, J=2.0 Hz, 1H), 7.22-7.21 (d, J=2.0 Hz, 1H), 6.71-6.69 (m,1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.55 (s, 3H), 1.99-1.93 (m, 1H),1.85-1.78 (m, 1H), 0.89-0.85 (m, 2H), 0.76-0.74 (m, 4H), 0.61-0.57 (m,2H).

Example 192:N-(4-((7-chloro-2-((5-(2-cyanopropan-2-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 192.1. To a suspension of sodium hydride (4.9 g,122.7 mmol, 1.5 equiv) in THF (50 mL) was added a solution of methyl3-nitro-1H-pyrazole-5-carboxylate (14 g, 81.82 mmol, 1.0 equiv) in THF(100 mL) at 0° C. It was stirred for 30 min followed by the addition of(2-chloromethoxyethyl)trimethylsilane (16.39 g, 98.18 mmol, 1.2 equiv).The reaction mixture was stirred at room temperature for 30 min. It waspoured over ice, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 12%ethyl acetate in hexane) to afford 192.1. ¹H NMR (DMSO-d₆, 400 MHz): δ7.66 (s, 1H), 5.85 (d, 2H), 3.90 (s, 3H), 3.63-3.59 (t, 2H), 0.85-0.81(t, 2H), 0.012 (s, 9H).

Synthesis of compound 192.2. To a solution of 192.1 (9.5 g, 31.52 mmol,1.0 equiv) in THF (100 mL) was added lithium borohydride (1 M in THF)(63 mL, 63.04 mmol, 2.0 equiv) slowly and the reaction mixture wasstirred at room temperature for 4 h. It was poured into a mixture ofice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 20%ethyl acetate in hexane) to afford 192.2. ¹H NMR (DMSO-d₆, 400 MHz): δ7.24 (s, 1H), 5.73 (s, 2H), 5.69-5.66 (m, 1H), 5.41-5.38 (m, 1H),4.62-4.60 (m, 1H), 4.46-4.45 (m, 2H), 3.59-3.55 (t, 2H), 0.04 (s, 9H).

Synthesis of compound 192.3. To a solution of 192.2 (5.1 g, 18.66 mmol,1.0 equiv) in DCM (50 mL) was added triethylamine (7.8 mL, 55.98 mmol,3.0 equiv) at 0° C. followed by the addition of methanesulfonyl chloride(2.15 mL, 27.99 mmol, 1.5 equiv). The reaction mixture was stirred atroom temperature for 2 h. It was poured into a mixture of ice-water,stirred and extracted with DCM. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 10% ethyl acetate in hexane)to afford 192.3. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.26 (s, 1H), 5.66 (s,2H), 4.98 (s, 2H), 4.78 (s, 2H), 3.63-3.58 (m, 2H), 0.02 (s, 9H).

Synthesis of compound 192.4. To a solution of 192.3 (3.0 g, 10.28 mmol,1.0 equiv) in acetonitrile (30 mL) was added potassium carbonate (3.54g, 25.7 mmol, 2.5 equiv) followed by the addition of trimethylsilylcyanide (2.54 g, 25.7 mmol, 2.5 equiv). The reaction mixture was stirredat 90° C. for 5 h. It was poured into a mixture of ice-water, stirredand extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 15% ethyl acetate in hexane)to afford 192.4. MS(ES): m/z 283.3 [M+H]⁺.

Synthesis of compound 192.5. To a solution of 192.4 (1.9 g, 6.73 mmol,1.0 equiv) in DMF (20 mL) was added sodium hydride (1.07 g, 26.92 mmol,4.0 equiv) at 0° C. and stirred for 20 min. To the mixture was addedmethyl iodide (3.82 g, 26.92 mmol, 4.0 equiv) and stirred at roomtemperature for 30 min. The reaction mixture was poured over crushedice, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 13% ethyl acetate inhexane) to afford 192.5. MS(ES): m/z 311.4 [M+H]⁺.

Synthesis of compound 192.6. To a solution of 192.5 (1.2 g, 3.87 mmol,1.0 equiv) in DCM (10 mL) was added trifluoroacetic acid (4 mL) at 0° C.and the mixture was stirred at room temperature for 6 h. The reactionmixture was poured over crushed ice-cold, saturated sodium bicarbonatesolution, stirred and extracted with DCM. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 40% ethyl acetate inhexane) to afford 192.6. MS(ES): m/z 181.2 [M+H]⁺.

Synthesis of compound 192.7. To a solution of 192.6 (0.6 g, 3.33 mmol,1.0 equiv) and 37.3 (0.768 g, 4.0 mmol, 1.2 equiv) in DMF (10 mL) wasadded cesium carbonate (3.2 g, 9.99 mmol, 3.0 equiv) and heated at80-90° C. for 5 h. The mixture was poured into a mixture of ice-water,stirred and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 45% ethyl acetate inhexane) to afford 192.7. MS (ES): m/z 277.3 [M+H]⁺.

Synthesis of compound 192.8. To a solution of 192.7 (0.180 g, 0.651mmol, 1.0 equiv) in ethanol:water (2:1, 10 mL) was added iron powder(0.182 g, 3.255 mmol, 5.0 equiv), followed by ammonium chloride (0.175g, 3.255 mmol, 5.0 equiv). The reaction mixture was heated at 30° C. for1 h. It was poured into a mixture of ice-water, filtered, and extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure to obtain 192.8. MS(ES): m/z 247.2 [M+H]⁺.

Synthesis of compound I-192. Compound I-192 was prepared from compound192.8 and 142.2 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m/z: 562.8[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.58 (s, 1H), 10.13 (s, 1H), 8.19(bs, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 6.77 (s, 1H), 6.66 (s, 1H), 4.98(bs, 1H), 4.73-4.61 (m, 4H), 3.92 (s, 3H), 3.11-3.09 (d, 4H), 2.04 (s,3H), 1.78 (s, 6H).

Example 193:N-(4-((2-((5-(tert-butyl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)amino)-7-chloro-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-193. Compound I-193 was prepared from compound164.3 and 142.2 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m/z: 551.8[M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.57 (s, 1H), 10.02 (s, 1H),8.18-8.17 (d, J=5.6 Hz, 1H), 7.63 (s, 1H), 6.65-6.63 (m, 1H), 6.51 (s,1H), 5.79 (s, 1H), 4.96-4.92 (m, 1H), 4.71 (bs, 2H), 4.58 (bs, 2H), 3.91(s, 3H), 2.80-2.70 (m, 2H), 2.02 (s, 3H), 1.55 (bs, 2H), 1.35 (s, 9H).

Example 194:N-(4-((2-((5-(2-cyanopropan-2-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-194. Compound I-194 was prepared from compound170.1 and 164.3 following the procedure described in the synthesis ofcompound I-128. The product was purified by preparative HPLC. MS(ES):m/z: 578.8 [M]⁺, ¹H NMR (CDCl₃, 400 MHz): δ 8.73 (bs, 1H), 8.15-8.14 (d,J=5.6 Hz, 1H), 7.93 (s, 1H), 7.16-7.03 (m, 1H), 6.62-6.61 (d, J=3.6 Hz,1H), 6.20 (s, 1H), 4.99-4.91 (m, 1H), 4.86 (s, 2H), 3.82 (s, 2H),2.93-2.88 (m, 2H), 2.22 (s, 3H), 1.79 (s, 3H), 1.30 (s, 6H), 0.91-0.88(m, 2H).

Example 195:(R)—N-(4-((2-((5-(tert-butyl)-4-(tetrahydrofuran-3-yl)thiazol-2-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamideand(S)—N-(4-((2-((5-(tert-butyl)-4-(tetrahydrofuran-3-yl)thiazol-2-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound (±)-I-195. Compound (±)-I-195 was prepared fromcompound (±)-187.7 and 155.3 following the procedure described in thesynthesis of compound I-108. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 70% ethyl acetate in hexane).MS(ES): m/z: 538.1 [M+H]⁺.

Synthesis of compounds I-195-a and I-195-b. The enantiomers of (±)-I-195were separated by HPLC (column: CHIRALPAK IC (250 mm×21 mm, 5 μm);mobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA inisopropanol:acetonitrile (70:30); flow rate=20 mL/min) to afford firsteluting fraction (I-195-a) and second eluting fraction (I-195-b).(*Absolute stereochemistry not determined.)

I-195-a. MS(ES): m/z: 538.1 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 12.12(s, 1H), 10.56 (s, 1H), 8.18-8.17 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.69(s, 1H), 6.66-6.64 (m, 1H), 4.01-3.95 (m, 2H), 3.91 (s, 3H), 3.84-3.80(m, 1H), 3.74 (s, 3H), 3.69-3.64 (m, 2H), 2.20-2.14 (m, 2H), 2.03 (s,3H), 1.41 (s, 9H).

I-195-b. MS(ES): m/z: 538.1 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 12.12(s, 1H), 10.56 (s, 1H), 8.18-8.17 (d, J=5.6 Hz, 1H), 7.96 (s, 1H), 7.68(s, 1H), 6.67-6.65 (m, 1H), 4.01-3.97 (m, 2H), 3.91 (s, 3H), 3.86-3.84(m, 1H), 3.74 (s, 3H), 3.69-3.66 (m, 2H), 2.20-2.14 (m, 2H), 2.03 (s,3H), 1.41 (s, 9H).

Example 196:N-(4-((2-((5-(tert-butyl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)amino)-7-methoxy-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound I-196. Compound I-196 was prepared from compound170.1 and 164.3 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 4.0% methanol in DCM). MS(ES): m/z: 573.5[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.86 (s, 1H), 9.79 (s, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.66-7.65 (d, J=2.0 Hz, 1H),6.70-6.68 (m, 1H), 6.53 (s, 1H), 4.96-4.92 (m, 1H), 4.71 (s, 2H), 4.58(s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 2.77-2.68 (m, 4H), 1.98-1.92 (m,1H), 1.36 (s, 9H), 0.77-0.75 (m, 4H).

Example 197:N-(4-((7-chloro-2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound I-197. Compound I-197 was prepared from compound181.4 and 61.4 following the procedure described in the synthesis ofcompound I-108. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 3.2% methanol in DCM). MS(ES): m/z: 506.6[M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.90 (s, 1H), 8.54 (s, 1H),8.30-8.29 (d, J=2.0 Hz, 1H), 8.21-8.20 (d, J=6.0 Hz, 1H), 8.02 (s, 1H),7.63-7.62 (d, J=2.4 Hz, 1H), 7.25-7.24 (d, J=2.0 Hz, 1H), 6.71-6.69 (m,1H), 3.96 (s, 3H), 3.55 (s, 3H), 1.98-1.95 (m, 1H), 1.84-1.79 (m, 1H),0.90-0.85 (m, 2H), 0.77-0.75 (m, 4H), 0.61-0.57 (m, 2H).

Example 198:(R)—N-(4-((2-((1-cyclobutyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamideand(S)—N-(4-((2-((1-cyclobutyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 198.1. To a solution of2-bromo-4-nitro-1H-imidazole (1.0 g, 5.21 mmol, 1.0 equiv) in DMF (10mL) was added sodium hydride (0.208 g, 5.21 mmol, 1.0 equiv) in portionsat room temperature and stirred for 1 h followed by the addition ofbromocyclobutane (1.4 g, 10.42 mmol, 2.0 equiv). The reaction mixturewas stirred at 90° C. for 48 h. It was poured into a mixture ofice-water, stirred and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 20%ethyl acetate in hexane) to afford 198.1. MS (ES): m/z 247.1 [M+H]⁺.

Synthesis of compound 198.2. A mixture of 198.1 (2.5 g, 10.16 mmol, 1.0equiv) 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.91 g,30.48 mmol, 3.0 equiv), potassium carbonate (7.01 g, 50.8 mmol, 5.0equiv), 1,4-dioxane (20 mL) and water (5 mL) was degassed by bubblingthrough a stream of argon for 10 min. Under the argon atmosphere[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex(0.829 g, 1.016 mmol, 0.1 equiv) was added, and degassed for another 5min. The reaction mixture was stirred at 100° C. for 1 h. It was cooledto room temperature and filtered through a pad of Celite®. The filtratewas transferred into water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,25% ethyl acetate in hexane) to afford 198.2. MS(ES): m/z 234.2 [M+H]⁺.

Synthesis of compound (±)-198.3. A mixture of 198.2 (0.500 g, 2.14 mmol,1.0 equiv), ammonium formate (0.539 g, 8.56 mmol, 4.0 equiv), palladiumhydroxide (0.350 g) in methanol (10 mL) and THF (6 mL) was stirred atroom temperature for 16 h under hydrogen pressure. The reaction mixturewas filtered through a pad of Celite® and washed with methanol. Thefiltrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 6%methanol in DCM) to afford (±)-198.3. MS(ES): m/z 208.2 [M+H]⁺.

Synthesis of compound (±)-I-198. Compound (±)-I-198 was prepared fromcompound (±)-198.3 and 169.7 following the procedure described in thesynthesis of compound I-136. The product was purified by flash columnchromatography on silica gel (CombiFlash®, 5.5% methanol in DCM).MS(ES): m/z: 515.3 [M+H]⁺.

Synthesis of compounds I-198-a and I-198-b. The enantiomers of (±)-I-198were separated by HPLC (column CHIRALPAK IB-N (250 mm×21 mm, 5 μm) andmobile phase: (A) 0.1% DEA in n-hexane, (B) 0.1% DEA inisopropanol:acetonitrile (70:30); flow rate=22 mL/min) to afford firsteluting fraction (I-198-a) and second eluting fraction (I-198-b).(*Absolute stereochemistry not determined.)

I-198-a. MS(ES): m/z: 515.3 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.83(s, 1H), 9.81 (s, 1H), 8.20-8.18 (d, J=5.6 Hz, 1H), 7.96-7.95 (d, J=2.0Hz, 1H), 7.64-7.63 (d, J=2.0 Hz, 1H), 7.61-7.60 (d, J=2.0 Hz, 1H), 7.58(s, 1H), 6.71-6.69 (m, 1H), 4.84-4.80 (m, 1H), 4.08-4.04 (m, 1H),3.89-3.82 (m, 1H), 3.80-3.75 (m, 1H), 3.67 (s, 3H), 3.61-3.57 (m, 1H),2.46 (bs, 2H), 2.38-2.34 (m, 2H), 2.28-2.25 (m, 1H), 2.16-2.13 (m, 1H),1.86-1.79 (m, 2H), 1.24 (bs, 2H), 0.77-0.75 (m, 4H).

I-198-b. MS(ES): m/z: 515.3 [M+H]⁺, LCMS purity: 95.42%, HPLC purity:95.00%, Chiral HPLC: 99.16%, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.91 (s, 1H),9.81 (s, 1H), 8.23-8.21 (d, J=5.6 Hz, 1H), 8.00 (bs, 1H), 7.75 (bs, 1H),7.65 (bs, 1H), 7.59 (bs, 1H), 6.76-6.74 (m, 1H), 4.96-4.93 (m, 1H), 4.06(bs, 1H), 3.96-3.94 (m, 1H), 3.80-3.76 (m, 1H), 3.59 (s, 3H), 3.61-3.57(m, 1H), 2.46 (bs, 2H), 2.34 (bs, 2H), 2.28-2.25 (m, 1H), 2.16-2.13 (m,1H), 2.00-1.98 (m, 2H), 1.24 (bs, 2H), 0.79-0.77 (m, 4H).

Example 199:N-(4-((2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(difluoromethyl)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 199.1. A mixture of 147.5 (0.170 g, 0.768 mmol,1.0 equiv), 14.5 (0.205 g, 1.15 mmol, 1.5 equiv) and potassium carbonate(0.317 g, 2.304 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 80° C. for1 h. The reaction mixture was cooled to room temperature, transferredinto ice-water, and product extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (CombiFlash®, 20%ethyl acetate in hexane) to afford 199.1. MS(ES): m/z 380.3 [M+H]⁺.

Synthesis of compound 199.2. A mixture of 199.1 (0.169 g, 0.445 mmol,1.0 equiv) and 10% palladium on carbon (0.100 g) in ethyl acetate (20mL) was stirred under hydrogen (1 atm) at rt for 2 h. The reactionmixture was filtered through a pad of Celite® and rinsed with ethylacetate. The filtrate was concentrated under reduced pressure to obtain199.2. MS(ES): m/z 350.3 [M+H]⁺.

Synthesis of compound 199.3. To a solution of 199.2 (0.090 g, 0.257mmol, 1.0 equiv) in THF (2 mL) was added 1,1′-thiocarbonyldiimidazole(0.228 g, 1.285 mmol, 5.0 equiv). The reaction mixture was stirred at80° C. for 1 h. It was cooled to room temperature and transferred intoice-water. The precipitated solids were collected by filtration andtriturated with hexane to obtain 199.3. MS(ES): m/z: 392.4 [M+H]⁺.

Synthesis of compound 199.4. To a solution of 199.3 (0.090 g, 0.229mmol, 1.0 equiv) in acetic acid (3.5 mL) was added aqueous hydrobromicacid (0.027 g, 0.343 mmol, 1.5 equiv) at 0° C. followed by bromine(0.145 g, 0.916 mmol, 4.0 equiv). The reaction mixture was stirred for15 min, and it was transferred into a saturated sodium bicarbonatesolution, stirred and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM)to afford 199.4. MS (ES): m/z 439.2 [M+H]+.

Synthesis of I-199. Compound I-193 was prepared from compound 199.4 and61.4 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.5% methanol in DCM). MS(ES): m/z: 522.7 [M+H]⁺, ¹HNMR (DMSO-d₆, 400 MHz): δ 10.93 (s, 1H), 8.65 (s, 1H), 8.33-8.32 (d,J=2.0 Hz, 1H), 8.24-8.23 (d, J=5.6 Hz, 1H), 8.19 (s, 1H), 7.68-7.67 (d,J=2.4 Hz, 1H), 7.54-7.28 (m, 1H), 7.27 (s, 1H), 6.73-6.71 (m, 1H), 3.84(s, 3H), 3.57 (s, 3H), 2.00-1.96 (m, 1H), 1.86-1.82 (m, 1H), 0.91-0.85(m, 2H), 0.78-0.76 (m, 4H), 0.63-0.59 (m, 2H).

Example 200:N-(4-((2-((1-(3,3-bis(hydroxymethyl)cyclobutyl)-5-(tert-butyl)-1H-pyrazol-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of compound 200.1. To a solution of 164.2 (0.4 g, 1.51 mmol,1.0 equiv) in DMSO (4 mL) and water (0.8 mL) was addedtrifluoromethanesulfonic acid (0.8 mL). The reaction mixture was stirredat room temperature for 3 h. It was poured over crushed ice-saturatedsodium bicarbonate solution, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,70% ethyl acetate in hexane) to afford 200.1. MS (ES): m/z 284.3 [M+H]⁺.

Synthesis of compound 200.2. To a solution of 200.2 (0.270 g, 0.952mmol, 1.0 equiv) in DMF (5 mL) was added sodium hydride (0.190 g, 4.76mmol, 5.0 equiv) in portions at 0° C. and stirred for 30 min followed bythe addition of benzyl bromide (0.813 g, 4.76 mmol, 5.0 equiv). Thereaction mixture was stirred at room temperature for 1 h. It was pouredinto a mixture of ice-water, stirred and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,20% ethyl acetate in hexane) to afford 200.2. MS (ES): m/z 464.5 [M+H]⁺.

Synthesis of compound 200.3. To a solution of 200.2 (0.240 g, 0.517mmol, 1.0 equiv) in ethanol:water (2:1, 8 mL) was added iron powder(0.144 g, 2.585 mmol, 5.0 equiv) followed by ammonium chloride (0.139 g,2.585 mmol, 5.0 equiv). The reaction mixture was heated at 90° C. for 1h. It was poured into a mixture of ice-water filtered and extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure toobtain 200.3. MS(ES): m/z 434.5 [M+H]⁺.

Synthesis of compound 200.4. Compound I-200 was prepared from compound200.3 and 169.7 following the procedure described in the synthesis ofcompound I-108. The product was further purified by flash columnchromatography on silica gel (CombiFlash®, 2.8% methanol in DCM) toafford 200.4. MS(ES): m/z: 741.9 [M+H]⁺.

Synthesis of I-200. To a solution of 200.4 (0.075 g, 0.090 mmol, 1.0equiv) in DCM (3 mL) was added trifluoromethanesulfonic acid (0.2 mL) at0° C. and stirred for 5 min. The reaction mixture was poured overcrushed ice-cold saturated sodium bicarbonate solution and extractedwith DCM. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 4.5% methanol in DCM) to afford I-200. MS(ES): m/z 561.3[M+H]⁺. ¹H NMR (DMSO-d₆, 400 MHz): δ 10.84 (s, 1H), 9.90 (s, 1H),8.19-8.18 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.65-7.64 (d,J=2.0 Hz, 1H), 6.70-6.68 (m, 1H), 6.56 (s, 1H), 4.96 (bs, 1H), 4.77 (bs,2H), 3.64 (s, 3H), 3.55 (s, 2H), 3.48 (s, 2H), 2.43-2.41 (m, 2H),2.23-2.18 (m, 2H), 1.98-1.95 (m, 1H), 1.37 (s, 9H), 0.77-0.75 (m, 4H).

Example 201:N-(4-((7-methoxy-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Synthesis of I-201. Compound I-201 was prepared from compounds 170.1 and54.3 following the procedure described in the synthesis of compoundI-108. The product was purified by flash column chromatography on silicagel (CombiFlash®, 2.6% methanol in DCM). MS(ES): m/z: 530.2 [M+H]⁺, ¹HNMR (DMSO-d₆, 400 MHz): δ 10.90 (s, 1H), 8.65 (s, 2H), 8.22-8.20 (d,J=5.6 Hz, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 6.72-6.71 (m,1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H), 1.97 (bs, 1H), 0.75 (bs,4H).

Example 202:N-(4-((7-chloro-2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-202. Compound I-202 was prepared from compounds 142.2 and61.4 following the procedure described in the synthesis of compoundI-128. The product was further purified by preparative HPLC. MS(ES):m/z: 480.4 [M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.60 (s, 1H), 8.56 (s,1H), 8.31 (s, 1H), 8.20-8.19 (d, J=4.8 Hz, 2H), 7.66 (s, 1H), 7.26 (bs,1H), 6.68-6.66 (m, 1H), 3.97 (s, 3H), 3.56 (s, 3H), 2.05 (s, 3H),1.86-1.81 (m, 1H), 0.91-0.85 (m, 2H), 0.62-0.59 (m, 2H).

Example I-203:N-(4-((7-chloro-2-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-203. Compound I-203 was prepared from compound 142.2 and14.8 following the procedure described in the synthesis of compoundI-128. The product was further purified by preparative HPLC. MS(ES):m/z: 603.5 [M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.61 (s, 1H), 9.68 (s,1H), 8.31 (s, 1H), 8.21-8.16 (m, 3H), 7.75-7.73 (d, J=8.4 Hz, 1H), 7.67(s, 1H), 6.68-6.67 (m, 1H), 4.01 (bs, 4H), 3.59 (s, 3H), 3.35 (bs, 4H),2.34 (s, 3H), 2.05 (s, 4H), 1.02-0.98 (t, 3H).

Example 204:N-(4-((7-chloro-1-methyl-2-((1-(3-morpholinopropyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 204.1. A mixture of 54.2 (8.0 g, 38.44 mmol, 1.0equiv) and 10% palladium on carbon (3.0 g) in methanol (30 mL) wasstirred under hydrogen (1 atm) at rt for 2 h. The reaction mixture wasfiltered through a pad of Celite® and rinsed with methanol. The filtratewas concentrated under reduced pressure to afford 204.1. MS(ES): m/z179.1 [M+H]⁺.

Synthesis of compound 204.2. A solution of 204.1 (6.5 g, 36.49 mmol, 1.0equiv) in toluene (25 mL) was added acetic anhydride (17 mL, 182.45mmol, 5.0 equiv) and the reaction mixture was heated to reflux for 2 h.It was cooled to rt and concentrated under reduced pressure. The residuewas purified by trituration with diethyl ether to afford 204.2. MS (ES):m/z 221.3 [M+H]⁺.

Synthesis of compound 204.3. To a solution of 3-morpholinopropan-1-ol(2.0 g, 13.77 mmol, 1.0 equiv) and triethylamine (4.79 mL, 34.42 mmol,2.5 equiv) in DCM (20 mL) at 0° C. was added methanesulfonyl chloride(1.4 mL, 17.90 mmol, 1.3 equiv). The reaction mixture was stirred atroom temperature for 1 h. It was transferred into ice-water, stirred andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure to afford 204.3. MS (ES): m/z 224.2 [M+H]⁺.

Synthesis of compound 204.4 To a solution of 204.2 (2.0 g, 9.08 mmol,1.0 equiv) in DMF (20 mL) was added potassium carbonate (3.75 g, 27.24mmol, 3.0 equiv), followed by 204.3 (2.43 g, 10.90 mmol, 1.2 equiv). Thereaction mixture stirred at 90° C. for 12 h. It was transferred intoice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 1.4% methanol in DCM)to afford 204.4. MS(ES): m/z 348.2 [M+H]⁺.

Synthesis of compound 204.5. A mixture of 204.4 (0.500 g, 1.44 mmol, 1.0equiv) and potassium carbonate (3.97 g, 28.8 mmol, 20 equiv) in methanol(10 mL) was heated to reflux for 16 h. The reaction mixture wastransferred into ice-water and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,2.6% methanol in DCM) to afford 204.5. MS(ES): m/z 306.3 [M+H]⁺.

Synthesis of compound 204.6. Compound 204.6 was prepared from 204.5following the procedure described in the synthesis of 11.8. The crudeproduct was used in the next step without further purification. MS(ES):m/z:348.3 [M+H]⁺.

Synthesis of I-204. To a solution of 141.4 (0.070 g, 0.227 mmol, 1.0equiv) and 204.6 (0.095 g, 0.272 mmol, 1.2 equiv) in THF (3 mL) wasadded potassium tert-butoxide (1 M in THF) (0.68 mL, 0.681 mmol, 3.0equiv) at 0° C. The reaction mixture was stirred at room temperature for16 h. It was transferred into ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 2.8% methanol in DCM) to afford I-204. MS(ES): m/z: 621.3[M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.61 (s, 1H), 8.87 (s, 1H),8.64-8.63 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.19-8.18 (d, J=5.6 Hz, 1H),8.14 (s, 1H), 7.65 (s, 1H), 6.67-6.65 (m, 1H), 4.17-4.14 (m, 2H), 3.98(s, 3H), 3.55 (bs, 4H), 2.32 (bs, 6H), 2.03 (s, 3H), 1.94-1.90 (m, 2H).

Example I-205:N-(4-((7-chloro-1-methyl-2-((4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 205.1. To a solution of4-amino-2-(trifluoromethyl)benzoic acid (3.0 g, 14.62 mmol, 1.0 equiv)and morpholine (1.91 g, 21.93 mmol, 1.5 equiv) in DCM (60 mL) was added1-hydroxybenzotriazole (2.96 g, 21.93 mmol, 1.5 equiv),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.18 g,21.93 mmol, 1.5 equiv), N,N-diisopropylethylamine (5.65 g, 43.86 mmol,3.0 equiv) and stirred at room temperature for 3 h. The reaction mixturewas poured over ice-water, stirred and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,1.2% methanol in DCM) to afford 205.1. MS (ES): m/z 275.2 [M+H]⁺.

Synthesis of compound 205.2. To a solution of 205.1 (1 g, 3.65 mmol, 1.0equiv) in THF (10 mL) was added borane-THF (1.04 mL, 10.95 mmol, 3.0equiv) at 0° C. The reaction mixture was heated to reflux for 3 h. Itwas cooled to room temperature, and a solution of 6 N hydrochloric acid(5 mL) was added. It was heated to reflux for another 2 h, cooled toroom temperature, poured into ice-water and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 1.0% methanol in DCM) to afford 205.2. MS(ES): m/z 261.3[M+H]⁺.

Synthesis of compound 205.3. Compound 205.3 was prepared from 205.2following the procedure described in the synthesis of 11.8. The crudeproduct was purified by flash column chromatography on silica gel(CombiFlash®, 40% ethyl acetate in hexane). MS(ES): m/z 303.3 [M+H]⁺.

Synthesis of I-205. Compound I-205 was prepared from 205.3 and 141.4following the procedure described in the synthesis of 1-204. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.8% methanol in DCM). MS(ES): m/z: 575.8 [M]⁺, ¹H NMR (DMSO-d₆, 400MHz): δ 10.62 (s, 1H), 9.71 (s, 1H), 8.31 (s, 1H), 8.21-8.16 (m, 3H),7.77-7.74 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 6.68-6.66 (m, 1H), 4.00 (s,3H), 3.62-3.60 (m, 6H), 2.41 (bs, 4H), 2.05 (s, 3H).

Example 206:N-(4-((7-methoxy-1-methyl-2-((1-(3-morpholinopropyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound 206.1. To compound 141.1 (1.0 g, 6.08 mmol, 1.0equiv) was added 0.5 M sodium methoxide solution in methanol (30 mL,15.2 mmol, 2.5 equiv) and copper iodide (0.231 g, 1.216 mmol, 0.2equiv). The reaction mixture was stirred at 110° C. for 24 h. It wascooled to room temperature, concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 18% ethyl acetate in hexane) to afford 206.1. MS(ES): m/z:161 [M+H]⁺.

Synthesis of compound 206.2. Concentrated sulfuric acid (6.6 mL, 6 vol.)was added dropwise to potassium persulfate (3.7 g, 13.74 mmol, 2.0equiv) at room temperature and stirred for 15 min. To this solution wasadded 206.1 (1.1 g, 6.87 mmol, 1.0 equiv) in portions, while maintainingtemperature between 30-40° C. The reaction mixture was stirred at roomtemperature for 24 h. It was transferred into crushed ice, stirred andbasified with saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 6-8% ethyl acetate in hexane) to afford 206.2. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.52 (s, 1H), 4.26 (s, 3H).

Synthesis of compound 206.3. To a solution of 206.2 (0.165 g, 0.867mmol, 1.0 equiv) in acetonitrile (1.5 mL) was added aqueous methylaminesolution (40%, 0.1 mL, 1.30 mmol, 1.5 equiv) dropwise at 0° C. Thereaction mixture was stirred at room temperature for 10-20 min. Thereaction mixture was poured over crushed ice-water and extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure toobtain 206.3. MS(ES): m/z: 201.9 [M+H]⁺.

Synthesis of compound 206.4. A mixture of 206.3 (0.112 g, 0.556 mmol,1.0 equiv), Int-1 (0.101 g, 0.668 mmol, 1.2 equiv) and potassiumcarbonate (0.230 g, 1.668 mmol, 3.0 equiv) in DMF (3 mL) was stirred at50-60° C. for 5-6 h. The reaction mixture was cooled to room temperatureand transferred into ice-water. The precipitated solids were collectedby filtration, rinsed with water and dried to afford 206.4. MS(ES): m/z334.2 [M+H]⁺.

Synthesis of compound 206.5. To a solution of compound 206.5 (0.140 g,0.420 mmol, 1.0 equiv) in isopropyl alcohol:water (8:2, 10 mL) was addediron powder (0.141 g, 2.52 mmol, 6.0 equiv) followed by acetic acid(0.151 g, 2.52 mmol, 6.0 equiv). The reaction mixture was heated at 100°C. for 3 h. It was filtered through a pad of Celite® and rinsed withisopropyl alcohol. The filtrate was concentrated under reduced pressure.The residue was purified by flash column chromatography on silica gel(CombiFlash®, 2.5% methanol in DCM) to afford 206.5. MS(ES): m/z 304.3[M+H]⁺.

Synthesis of I-206. Compound I-206 was prepared from 206.5 and 204.6following the procedure described in the synthesis of 1-204. The productwas purified by flash column chromatography on silica gel (CombiFlash®,2.5% methanol in DCM). MS(ES): m/z: 617.5 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz): δ 10.60 (s, 1H), 8.68 (s, 1H), 8.66-8.65 (d, J=1.6 Hz, 1H),8.20-8.19 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H),6.69-6.67 (m, 1H), 4.18-1.14 (m, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 3.56(bs, 4H), 2.34 (bs, 6H), 2.05 (s, 3H), 1.95-1.92 (m, 2H).

Example 207:N-(4-((7-cyano-2-((5-cyclopropyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-207. A mixture of 1-202 (0.190 g, 0.395 mmol, 1.0 equiv),zinc dust (0.005 g, 0.079 mmol, 0.2 equiv) and zinc cyanide (0.231 g,1.975 mmol, 5.0 equiv) in dimethylacetamide (6 mL) was degassed bybubbling through argon for 10 min. Under argon atmosphere,1,1′-ferrocenediyl-bis(diphenylphosphine) (0.065 g, 0.118 mmol, 0.3equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.054 g, 0.059mmol, 0.15 equiv) were added and degassed for another 5 min. Thereaction mixture was stirred at 170° C. in a microwave reactor for 30min. It was cooled to room temperature, transferred into water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 2.7% methanol in DCM) toafford I-207. MS(ES): m/z:471.2 [M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.67(s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.26-8.24 (d, J=6.0Hz, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 6.77-6.76 (d, J=3.2 Hz, 1H), 3.94(s, 3H), 3.57 (s, 3H), 2.07 (s, 3H), 1.84 (bs, 1H), 0.90-0.87 (m, 2H),0.61-0.60 (m, 2H).

Example 208:N-(4-((7-chloro-2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-208. To a solution of 141.4 (0.500 g, 1.62 mmol,1.0 equiv) and 40.6 (0.370 g, 1.79 mmol, 1.1 equiv) in THF (5 mL) wasadded potassium tert-butoxide (1 M in THF, 3.24 mL, 3.24 mmol, 2.0equiv) at 0° C. The reaction mixture was stirred at room temperature for30 min. The reaction mixture was transferred into ice-water, and productwas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was dissolved in THF (5 mL) andadded N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.928 g, 4.86 mmol, 3.0 equiv). The reaction mixture was heated at 70°C. for 4 h. The reaction mixture transferred into water, and product wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 3.0% methanol in DCM) toafford I-208. MS(ES): m/z: 481.6 [M+H]⁺.

Example 209:N-(4-((7-chloro-2-((4,4-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-c]pyridin-2-yl)amino)-1-methyl-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-209. Compound I-209 was prepared from I-208 following theprocedure described in the synthesis of 1-207. The product was purifiedby flash column chromatography on silica gel (CombiFlash®, 3.2% methanolin DCM). MS(ES): m/z:472.0 [M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.65 (s,1H), 10.38 (s, 1H), 8.24-8.23 (d, J=5.2 Hz, 2H), 7.76 (s, 1H), 7.09-7.08(d, J=6.0 Hz, 1H), 6.74 (bs, 1H), 3.98 (bs, 2H), 3.90 (s, 3H), 2.06 (s,3H), 1.69 (bs, 2H), 1.56 (bs, 2H), 1.34 (s, 6H).

Example 210:N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of compound I-210. Compound I-210 was prepared from compound142.2 and 54.3 following the procedure described in the synthesis ofcompound I-128. The product was purified by flash column chromatographyon silica gel (CombiFlash®, 2.3% methanol in DCM). MS(ES): m/z:508.2[M]⁺.

Example 211:N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Synthesis of I-211. Compound I-211 was prepared from I-210 following theprocedure described in the synthesis of 1-207. The product was furtherpurified by flash column chromatography on silica gel (CombiFlash®, 2.5%methanol in DCM). MS(ES): m/z:499.0 [M]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ10.67 (s, 1H), 9.06 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.25-8.23 (d,J=5.6 Hz, 1H), 8.19 (s, 1H), 7.75 (s, 1H), 6.76-6.75 (m, 1H), 3.96 (s,3H), 3.66 (s, 3H), 2.06 (s, 3H).

Example 212:(S)—N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)acetamideand(R—N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)acetamide

Synthesis of compound (±)-212.1. To a solution of δ-valerolactone (10.0g, 99.88 mmol, 1.0 equiv) in DCM (300 mL) was added diisobutylaluminiumhydride (1M in DCM, 120 mL, 119.85 mmol, 1.2 equiv) at −78° C. andstirred for 2 h. The reaction was quenched by the addition of methanol(30 mL) followed by saturated potassium sodium tartrate solution (100mL). The precipitated solids were removed by filtration and the filtratewas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford (±)-212.1. It was used in the next stepwithout further purification. ¹H NMR (DMSO-d₆, 400 MHz): δ 6.17-6.15 (m,1H), 4.65 (bs, 1H), 3.84-3.81 (m, 1H), 3.38-3.34 (m, 1H), 1.73-1.57 (m,2H), 1.45-1.32 (m, 4H).

Synthesis of compound (±)-212.2. A mixture of (±)-212.1 (8.0 g, 78.33mmol, 1.0 equiv), malonic acid (9.78 g, 94 mmol, 1.2 equiv), pyridine(13 mL, 161 mmol, 2.06 equiv) and piperidine (0.77 mL, 7.833 mmol, 0.1equiv) was stirred at room temperature for 16 h. It was stirred at 105°C. for another 4 h. The reaction mixture was cooled to rt, transferredinto aqueous hydrochloric acid (2 N), and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel (CombiFlash®,50% ethyl acetate in hexane) to afford (±)-212.2. ¹H NMR (CDCl₃, 400MHz): δ 4.24-4.11 (m, 1H), 3.71-3.68 (m, 1H), 3.40 (bs, 1H), 2.29-2.28(m, 1H), 2.06 (bs, 1H), 1.72-1.67 (m, 1H), 1.61-1.57 (m, 4H), 1.29-1.26(m, 1H).

Synthesis of compound (±)-212.3. To a solution of (±)-212.2 (1.6 g, 11.1mmol, 1.0 equiv) and Int-1.3 (2.44 g, 12.21 mmol, 1.1 equiv) in DMF (20mL) was added HATU (6.32 g, 16.65 mmol, 1.5 equiv) and reaction mixturestirred at room temperature for 30 min. To this was addedN,N-diisopropylethylamine (4.8 mL, 27.75 mmol, 2.5 equiv). The reactionmixture was stirred at room temperature for 16 h. It was poured intoice-water and extracted with ethyl acetate. The combined organic layerswere washed with brine solution, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 45% ethyl acetate inhexane) to afford (±)-212.3. MS(ES): m/z 327.2 [M+H]⁺.

Synthesis of compound (±)-212.4. A mixture of compound (±)-212.3 (0.565g, 1.73 mmol, 1.0 equiv) and 10% palladium on carbon (0.25 g) inmethanol (15 mL) was stirred under hydrogen (1 atm) for 2 h. Thereaction mixture was filtered through a pad of Celite® and washed withmethanol. The filtrate was concentrated under reduced pressure to afford(±)-212.4. MS(ES): m/z 237.5 [M+H]⁺.

Synthesis of compound (±)-212.5. A mixture of (±)-212.4 (0.340 g, 1.44mmol, 1.0 equiv), 141.3 (0.295 g, 1.44 mmol, 1.0 equiv) and potassiumcarbonate (0.397 g, 2.88 mmol, 2.0 equiv) in DMF (5 mL) was stirred atroom temperature for 1 h. It was transferred into water and extractedwith ethyl acetate. The combined organic layers were washed with brinesolution, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 3.5% methanol in DCM) toafford (±)-212.5. MS(ES): m/z 422.2 [M+H]⁺.

Synthesis of compound (±)-212.6. To a solution of (±)-212.5 (0.260 g,0.616 mmol, 1.0 equiv) in ethanol:water (2:1, 10 mL) was added ironpowder (0.172 g, 3.08 mmol, 5.0 equiv) followed by ammonium chloride(0.166 g, 3.08 mmol, 5.0 equiv). The reaction mixture was stirred at 80°C. for 1 h. It was transferred into ice-water, filtered and extractedwith ethyl acetate. The combined organic layers were washed with brinesolution, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (CombiFlash®, 4.2% methanol in DCM) toafford (±)-212.6. MS(ES): m/z 392.1 [M+H]⁺.

Synthesis of compound (±)-I-212. Compound (±)-I-212 was prepared from(±)-212.6 and 54.4 following the procedure described in the synthesis of1-204. The product was purified by flash column chromatography on silicagel (CombiFlash®, 3.3% methanol in DCM). MS(ES): m/z: 592.5 [M+H]⁺.

Synthesis of compounds I-212a and I-212b. The racemate (±)-I-212 wasseparated by HPLC (column CHIRALCEL OX-H (250 mm*21 mm, 5 μm); mobilephase: (A) 0.1% DEA in n-hexane (B) 0.1% DEA in isopropanol:acetonitrile(70:30); flow rate: 20 mL/min) to afford first eluting fraction(I-212-a) and second eluting fraction (I-212-b). (*Absolutestereochemistry not determined.)

I-212-a: MS(ES): m/z: 592.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz): δ 10.52(s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 8.21-8.20 (d, J=5.2Hz, 1H), 8.16 (s, 1H), 7.68 (s, 1H), 6.71-6.70 (d, J=4.8 Hz, 1H), 4.00(s, 3H), 3.82-3.79 (m, 1H), 3.68 (s, 3H), 3.30 (bs, 2H), 2.42-2.34 (m,2H), 1.74 (bs. 1H), 1.58-1.55 (m, 1H), 1.43 (bs, 2H), 1.25-1.18 (m, 2H).

I-212-b: MS(ES): m/z: 592.2 [M+H]⁺, ¹H NMR (DMSO-d₆, 400 MHz): δ 10.18(s, 1H), 8.66-8.63 (m, 2H), 8.22-8.21 (d, J=2.0 Hz, 1H), 8.19 (s, 1H),8.06 (s, 1H), 7.69 (s, 1H), 6.69-6.67 (m, 1H), 4.02 (s, 3H), 3.86-3.83(m, 1H), 3.69 (s, 3H), 3.36 (bs, 2H), 2.44-2.40 (m, 2H), 1.76 (bs. 1H),1.63-1.60 (m, 1H), 1.47 (bs, 2H), 1.26-1.18 (m, 2H).

Example 213:N-(4-((7-chloro-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)-3-morpholinopropanamide

Synthesis of compound 213.1. To a solution of Int-1.3 (5.0 g, 24.97mmol, 1.0 equiv) and pyridine (6.0 mL, 74.91 mmol, 3.0 equiv) in DCM (50mL) at 0° C. was added 3-chloropropionyl chloride (9.5 mL, 99.88 mmol,4.0 equiv) dropwise and the mixture was stirred at room temperature for16 h. It was transferred into water and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford213.1. MS(ES): m/z 291.5 [M+H]⁺.

Synthesis of compound 213.2. A mixture of 213.1 (6.0 g, 20.64 mmol, 1.0equiv), morpholine (8.99 g, 103.18 mmol, 5.0 equiv) and potassiumcarbonate (8.54 g, 61.92 mmol, 3.0 equiv) in DMF (60 mL) was stirred at100° C. for 1 h. It was cooled to room temperature, transferred intowater and extracted with ethyl acetate. The combined organic layers werewashed with brine solution, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (CombiFlash®, 2.5% methanol in DCM)to afford 213.2. MS(ES): m/z 342.4 [M+H]⁺.

Synthesis of compound 213.3. A mixture of 213.2 (1.2 g, 3.51 mmol, 1.0equiv) and 20% palladium hydroxide (0.6 g) in methanol (15 mL) wasstirred under hydrogen (1 atm) at rt for 1 h. The reaction mixture wasfiltered through a pad of Celite® and rinsed with methanol. The filtratewas concentrated under reduced pressure. The residue was purified byflash column chromatography on silica gel (CombiFlash®, 3.5% methanol inDCM) to afford 213.3. MS(ES): m/z 252.2 [M+H]⁺.

Synthesis of compound 213.4. A mixture of 213.3 (0.650 g, 2.59 mmol, 1.0equiv), 141.3 (0.531 g, 2.59 mmol, 1.0 equiv) and potassium carbonate(0.714 g, 5.18 mmol, 2.0 equiv) in DMF (7 mL) was stirred at 100° C. for1 h. It was transferred into water and extracted with ethyl acetate. Thecombined organic layers were washed with brine solution, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(CombiFlash®, 3.3% methanol in DCM) to afford 213.4. MS(ES): m/z 437.5[M+H]⁺.

Synthesis of compound 213.5. To a solution of 213.4 (0.300 g, 0.686mmol, 1.0 equiv) in ethanol:water (2:1, 8 mL) was added iron powder(0.192 g, 3.43 mmol, 5.0 equiv) followed by ammonium chloride (0.185 g,3.43 mmol, 5.0 equiv). The reaction mixture was stirred at 80° C. for 1h. It was transferred into ice-water, filtered and extracted with ethylacetate. The combined organic layers were washed with brine solution,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel (CombiFlash®, 4.5% methanol in DCM) to afford 213.5. MS(ES):m/z 407.5 [M+H]⁺.

Synthesis of I-213. Compound I-213 was prepared from 213.5 and 54.4following the procedure described in the synthesis of 1-204. The productwas purified by flash column chromatography on silica gel (CombiFlash®,6.5% methanol in DCM). MS(ES): m/z: 607.2 [M+H]⁺, ¹H NMR (DMSO-d₆, 400MHz): δ 10.78 (s, 1H), 8.86 (s, 1H), 8.64 (s, 1H), 8.25 (s, 1H),8.22-8.21 (d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 6.71-6.70 (m,1H), 4.00 (s, 3H), 3.67 (s, 3H), 3.56 (s, 4H), 2.56 (bs, 4H), 2.38 (bs,4H).

Example 215:N-(4-((7-methoxy-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)acetamide

Compound I-215 is prepared from 206.5 and 54.4 following the proceduredescribed in the synthesis of 1-204.

Example 216:N-(4-((7-cyano-1-methyl-2-((1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)amino)-1H-imidazo[4,5-b]pyridin-6-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Compound I-216 is prepared from 181.4 and 54.3 according to theprocedure described in the synthesis of 1-197, followed by cyanationaccording to the procedure described in the synthesis of 1-207.

JAK2 Binding Assay

JAK2 (JH1domain-catalytic, Y1007F,Y1008F) kinase was expressed asN-terminal fusion to the DNA binding domain of NFkB in transientlytransfected HEK293 cells and subsequently tagged with DNA for qPCRdetection. Streptavidin-coated magnetic beads were treated withbiotinylated small molecule ligands for 30 minutes at room temperatureto generate affinity resins for kinase assays. The liganded beads wereblocked with excess biotin and washed with blocking buffer (SeaBlock(Pierce), 1% BSA, 0.05% Tween 20, 1 mmol/L DTT) to remove unbound ligandand to reduce nonspecific phage binding. Binding reactions wereassembled by combining kinases, liganded affinity beads, and testcompounds in 1× binding buffer (1×PBS, 0.05% Tween 20, 0.1% BSA, 1mmol/L DTT). Test compound was prepared as 111× stocks in 100% DMSO anddirectly diluted into the assay wells. All reactions were performed inpolypropylene 384-well plates in a final volume of 0.02 mL. The assayplates were incubated at room temperature with shaking for 1 hour andthe affinity beads were washed with wash buffer (1×PBS, 0.05% Tween 20).The beads were then re-suspended in elution buffer (1×PBS, 0.05% Tween20, 0.5 μmol/L non-biotinylated affinity ligand) and incubated at roomtemperature with shaking for 30 minutes. The kinase concentration in theeluate was measured by qPCR.

Results of the JAK2 JH1 Domain Binding Assay described above arepresented in Table 2. Compounds denoted as “A” had a K_(d)<10 nM;compounds denoted as “B” had a K_(d)≥10 nM and <50 nM; compounds denotedas “C” had a K_(d)≥50 nM and <1 μM; compounds denoted as “D” had aK_(d)≥1 μM and <5 μM; and compounds denoted as “E” had a K_(d)≥5 μM.

TABLE 2 Results of JAK2 Binding Assay Compound JAK2 K_(d) I-1 A I-2 AI-3 A I-4 C I-5 B I-6 A I-7 C I-8 C I-9 D I-10 C I-11 B I-12-a B I-12-bB I-13 E I-14 A I-15 B I-16 C I-17 C I-18 B I-19 C I-20 A I-21 A I-22 AI-23 D I-24 A I-25 A I-26 A I-27 A I-28 A I-29 A I-30 A I-31 A I-32 AI-33 C I-34 A I-35 C I-36-a C I-36-b C I-37 A I-38 C I-39 A I-40 A I-41A I-42 A I-43 D I-44 C I-45-a E I-45-b E I-46 B I-47 B I-48 B I-49 BI-50-a C I-50-b C I-51 D I-52 A I-53 A I-54 A I-55 A I-56 D I-57 CI-58-a B I-58-b C I-59-a B I-59-b B I-60-a B I-60-b A I-61 A I-62 A I-63A I-64 B I-65 A I-66-a A I-66-b A I-67-a A I-67-b A I-68-a A I-68-b AI-69 A I-70 A I-71 A I-72 A I-73 A I-74 C I-75-a A I-75-b A I-76-a AI-76-b B I-77-a A I-77-b A I-78-a A I-78-b B I-79-a A I-79-b A I-80 AI-81 A I-82 D I-83 E I-84 A I-85 A I-86 C I-87-a C I-87-b C I-88 D I-89B I-90 A I-91 D I-92 B I-93 B I-94 A I-95 C I-96 B I-97 B I-98 A I-99 AI-100 A I-101 C I-103 A I-104 A I-105 C I-106 C I-108 A I-109 A I-110 AI-111 A I-112-a A I-112-b A I-113 B I-114 A I-115 A I-116 A I-117-a AI-117-b A I-118 A I-119 A I-120 B I-121 B I-122 A I-123 A I-124 A I-125A I-126 A I-127 A I-128-a C I-128-b C I-129-a B I-129-b A I-130 A I-131A I-132 A I-133 A I-134 A I-135-a A I-135-b B I-136 A I-137 A I-138 AI-139 A I-140 A I-141 A I-142 A I-143 B I-144 B I-145 A I-146 A I-147 AI-148-a D I-148-b D I-149 A I-150 A I-151 A I-152 A I-153 A I-154 AI-155 A I-156 A I-157 A I-158 A I-159 A I-160 A I-161 A I-162-a AI-162-b B I-163-a A I-163-b A I-164 A I-165 A I-166 A I-167 A I-168 AI-169-b B I-170 A I-171 A I-172-a A I-172-b B I-173 B I-174 C I-175-a AI-175-b C I-176-a A I-176-b A I-177 A I-178 A I-179 A I-180 B I-181 AI-182 A I-183 A I-184 A I-185 A I-186 A I-187-a A I-187-b A I-188 AI-189-a A I-189-b A I-190-a A I-190-b A I-191 A I-192 A I-193 A I-194 AI-195-a A I-195-b A I-196 A I-197 A I-198-a A I-198-b A I-199 A I-200 AI-201 A I-202 A I-203 A I-204 A I-205 B I-206 A I-207 B I-208 A I-209 AI-210 A I-211 A

JAK Family Selectivity Assays

Provided compounds are evaluated for selectivity by comparing their JAK2binding affinity (K_(d)) in the above JAK2 Binding Assay with theirbinding affinity (K_(d)) for one or more other kinases. Binding affinityfor other kinases is determined as follows: Kinase-tagged T7 phagestrains are prepared in an E. coli host derived from the BL21 strain. E.coli are grown to log-phase and infected with T7 phage and incubatedwith shaking at 32° C. until lysis. The lysates are centrifuged andfiltered to remove cell debris. The remaining kinases are produced inHEK-293 cells and subsequently tagged with DNA for qPCR detection.Streptavidin-coated magnetic beads are treated with biotinylated smallmolecule ligands for 30 minutes at room temperature to generate affinityresins for kinase assays. The liganded beads are blocked with excessbiotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05%Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specificbinding. Binding reactions are assembled by combining kinases, ligandedaffinity beads, and test compounds in 1× binding buffer (20% SeaBlock,0.17×PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 111×stocks in 100% DMSO. Kds are determined using an 11-point 3-foldcompound dilution series with three DMSO control points. All compoundsfor K_(d) measurements are distributed by acoustic transfer (non-contactdispensing) in 100% DMSO. The compounds are then diluted directly intothe assays such that the final concentration of DMSO is 0.9%. Allreactions are performed in polypropylene 384-well plate. Each has afinal volume of 0.02 ml. The assay plates are incubated at roomtemperature with shaking for 1 hour and the affinity beads are washedwith wash buffer (1×PBS, 0.05% Tween 20). The beads are thenre-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates ismeasured by qPCR. Compounds that exhibit a better binding affinity forJAK2 compared to one or more other kinases are considered to beJAK2-selective compounds. In some embodiments, provided compounds may beJAK2-selective over one or more of the following kinases: JAK1, JAK3,and Tyk2.

SET2-pSTAT5 Cellular Assay

This assay measures inhibition of JAK2-mediated pSTAT5 signaling inconstitutively active essential thrombocytopenia cells carrying theV617F mutation. Cells are harvested from a flask into cell culturemedium, and the number of cells is counted. The cells are diluted withculture medium and 100 μL of cell suspension (50000/well) is added intoeach well of a 96-well cell culture plate. A solution of test compoundis added to the assay plate. The plates are covered with a lid andplaced in a 37° C. 5% CO₂ incubator for 4 hours. After 4 hours, thecells are spun, and the cell pellets are re-suspended with 100 μL coldPBS. Then, the cells are spun again at 4° C. and 4000 rpm for 5 min. PBSis aspirated, and 25 μL lysis buffer (with protease and phosphataseinhibitor cocktail) is added to each cell pellet. The cell lysate isshaken at 4° C. for 20 min to fully lyse the cells. The cell lysate isspun at 4° C. and 4000 rpm for 15 min, and then the supernatant istransferred into a new plate and stored at −80° C. Meso-scale discovery(MSD) is used to analyze plates as follows: a standard MSD plate iscoated with capture antibody in PBS (40 μL/well) and is incubated at 4°C. overnight with shaking. The MSD plate is washed three times with 150μL/well of 1×MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20detergent, TBST). The MSD plates are then blocked with 150 μL ofblocking buffer (5% BSA in TBST) and shaken for 1 h at room temperatureand 600 rpm. The MSD plate is washed three times with 150 μL/well of1×MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates(25 μL/well) and shaken for 1 h at room temperature and 600 rpm. The MSDplate is washed three times with 150 μL/well of 1×MSD Wash Buffer(TBST). Detection antibody (prepared in Antibody Detection buffer, 1%BSA in 1×TBST) is then added to the MSD plates, and they are shaken for1 h at room temperature and 600 rpm. The MSD plate is washed three timeswith 150 μL/well of 1×MSD Wash Buffer (TBST). A secondary detectionantibody (prepared in Antibody Detection buffer, 1% BSA in 1×TBST) isthen added to the MSD plates, and they are shaken for 1 h at roomtemperature and 600 rpm. The MSD plate is washed three times with 150μL/well of 1×MSD Wash Buffer (TBST). MSD reading buffer (lx) is added tothe plates (150 μL/well), and they are diluted from 4× with water. Theplates are imaged using an MSD imaging instrument according to themanufacturer's instructions.

Caco2 Permeability Assay

Preparation of Caco-2 Cells: 50 μL and 25 mL of cell culture medium areadded to each well of a Transwell® insert and reservoir, respectively.Then, the HTS Transwell® plates are incubated at 37° C., 5% CO₂ for 1hour before cell seeding. Caco-2 cell cells are diluted to 6.86×105cells/mL with culture medium, and 50 μL of cell suspension are dispensedinto the filter well of the 96-well HTS Transwell® plate. Cells arecultivated for 14-18 days in a cell culture incubator at 37° C., 5% CO₂,95% relative humidity. Cell culture medium is replaced every other day,beginning no later than 24 hours after initial plating.

Preparation of Stock Solutions: 10 mM stock solutions of test compoundsare prepared in DMSO. The stock solutions of positive controls areprepared in DMSO at the concentration of 10 mM. Digoxin and propranololare used as control compounds in this assay.

Assessment of Cell Monolayer Integrity: Medium is removed from thereservoir and each Transwell® insert and is replaced with prewarmedfresh cuture medium. Transepithelial electrical resistance (TEER) acrossthe monolayer is measured using Millicell Epithelial Volt-Ohm measuringsystem (Millipore, USA). The Plate is returned to the incubator once themeasurement is done. The TEER value isss calucated according to thefollowing equation: TEER measurement (ohms)×Area of membrane (cm²)=TEERvalue (ohm·cm²). A TEER value greater than 230 ohm·cm² indicates awell-qualified Caco-2 monolayer.

Assay Procedure: The Caco-2 plate is removed from the incubator andwashed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and thenincubated at 37° C. for 30 minutes. The stock solutions of controlcompounds are diluted in DMSO to get 1 mM solutions and then dilutedwith HBSS (10 mM HEPES, pH 7.4) to get 5 μM working solutions. The stocksolutions of the test compounds are diluted in DMSO to get 1 mMsolutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) toget 5 μM working solutions. The final concentration of DMSO in theincubation system is 0.5%. To determine the rate of drug transport inthe apical to basolateral direction. 75 μL of 5 μM working solutions oftest compounds are added to the Transwell® insert (apical compartment)and the wells in the receiver plate (basolateral compartment) are filledwith 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine therate of drug transport in the basolateral to apical direction, 235 μL of5 μM working solutions of test compounds are added to the receiver platewells (basolateral compartment) and then the Transwell® inserts (apicalcompartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM workingsolution to wells of the 96-deepwell plate, followed by the addition of200 μL cold methanol containing appropriate internal standards (IS). Theplates are incubated at 37° C. for 2 hours. At the end of theincubation, 50 μL samples from donor sides (apical compartment for Ap→Blflux, and basolateral compartment for Bl→Ap) and receiver sides(basolateral compartment for Ap→Bl flux, and apical compartment forBl→Ap) are transferred to wells of a new 96-well plate, followed by theaddition of 4 volume of cold acetonitrile or methanol containingappropriate internal standards (IS). Samples are vortexed for 5 minutesand then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 μL ofthe supernatant is mixed with an appropriate volume of ultra-pure waterbefore LC-MS/MS analysis. To determine the Lucifer Yellow leakage after2 hour transport period, stock solution of Lucifer yellow is prepared inultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reachthe final concentration of 100 μM. 100 μL of the Lucifer yellow solutionis added to each Transwell® insert (apical compartment), followed byfilling the wells in the receiver plate (basolateral compartment) with300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37° C.for 30 minutes. 80 μL samples are removed directly from the apical andbasolateral wells (using the basolateral access holes) and transferredto wells of new 96 wells plates. The Lucifer Yellow fluorescence (tomonitor monolayer integrity) signal is measured in a fluorescence platereader at 485 nM excitation and 530 nM emission.

Cytotoxicity Assay

HEK293T cells are harvested from flask into cell culture medium, andthen the cells are counted. The cells are diluted with culture medium tothe desired density, and 40 μL of cell suspension is added into eachwell of a 384-well cell culture plate. The plates are covered with a lidand spun at room temperature at 1,000 RPM for 1 minute and thentransferred into 37° C. 5% CO₂ incubator overnight. Test compounds aredissolved at 10 mM DMSO stock solution. 45 μL of stock solution is thentransferred to a 384 PP-plate. A 3-fold, 10-point dilution is performedvia transferring 15 μL compound into 30 μL DMSO by using TECAN (EVO200)liquid handler. The plates are spun at room temperature at 1,000 RPM for1 minute and shaken on a plate shaker for 2 minutes. 40 nL of dilutedcompound is transferred from compound source plate into the cell plateby using liquid handler Echo550. After compound treatment for 48 hours,CTG detection is performed for compound treatment plates: the plates areremoved from incubators and equilibrated at room temperature for 15minutes. 30 μL of CellTiter-Glo reagent is added into each well to bedetected. The plates are then placed at room temperature for 30 minfollowed by reading on EnVision. Inhibition activity is calculated withthe following formula: % Inhibition=100×(LumHC−LumSample)/(LumHC−LumLC),wherein HC is reading obtained from cells treated with 0.1% DMSO onlyand LC is reading from cells treated with 10 μL staurosporine. IC₅₀values are calculated using XLFit (equation 201).

Hepatocyte Stability Assay

10 mM stock solutions of test compound and positive control are preparedin DMSO. Stock solutions are diluted to 100 μM by combining 198 μL of50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamilis used as positive control in the assay. Vials of cryopreservedhepatocytes are thawed in a 37° C. water bath with gently shaking. Thecontents are poured into the 50 mL thawing medium conical tube. Vialsare centrifuged at 100 g for 10 minutes at room temperature. Thawingmedium is aspirated and hepatocytes are re-suspended with serum-freeincubation medium to yield ˜1.5×106 cells/mL. Cell viability and densityare counted using a Trypan Blue exclusion, and then cells are dilutedwith serum-free incubation medium to a working cell density of 0.5×106viable cells/mL. A portion of the hepatocytes at 0.5×106 viable cells/mLare boiled for 5 min prior to adding to the plate as negative control toeliminate the enzymatic activity so that little or no substrate turnovershould be observed. Aliquots of 198 μL hepatocytes are dispensed intoeach well of a 96-well non-coated plate. The plate is placed in theincubator for approximately 10 minutes. Aliquots of 2 μL of the 100 μMtest compound and 2 μL positive control are added into respective wellsof a non-coated 96-well plate to start the reaction. The finalconcentration of test compound is 1 μM. This assay is performed induplicate. The plate is incubated in the incubator for the designed timepoints. 25 μL of contents are transferred and mixed with 6 volumes (150μL) of cold acetonitrile with internal standard (100 nM alprazolam, 200nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate thereaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samplesare centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of thesupernatants are used for LC-MS/MS analysis.

Kinetic Solubility Assay

Stock solutions of test compounds are prepared in DMSO at theconcentration of 10 mM, and a stock solution of control compound isprepared in DMSO at the concentration of 30 mM. Diclofenac is used aspositive control in the assay. 30 μL stock solution of each compound isplaced into their a 96-well rack, followed by adding 970 μL of PBS at pH4.0 and pH 7.4 into each vial of the cap-less solubility sample plate.This study is performed in duplicate. One stir stick is added to eachvial and then vials are sealed using a molded PTDE/SIL 96-Well PlateCover. The solubility sample plate is transferred to the Thermomixercomfort plate shaker and incubated at RT for 2 hours with shaking at1100 rpm. After 2 hours incubation, stir sticks are removed using a bigmagnet and all samples from the solubility sample plate are transferredinto the filter plate. All the samples are filtered by vacuum manifold.The filtered samples are diluted with methanol. Samples are analyzed byLC-MS/MS and quantified against a standard of known concentration inDMSO using LC coupled with Mass spectral peak identification andquantitation. The solubility values of the test compounds are calculatedas follows, wherein INJ VOL is injection volume, DF is dilution factor,and STD is standard:

$\lbrack{Sample}\rbrack = \frac{{AREA}_{Sample} \times {INJ}\mspace{11mu}{VOL}_{Std} \times {DF}_{Sample} \times \lbrack{STD}\rbrack}{{AREA}_{Std} \times {INJ}\mspace{14mu}{VOL}_{Sample}}$

Plasma Protein Binding Assay

Working solutions of test compounds and control compound are prepared inDMSO at the concentration of 200 μM, and then the working solutions arespiked into plasma. The final concentration of compound is 1 μM. Thefinal concentration of DMSO is 0.5%. Ketoconazole is used as positivecontrol in the assay. Dialysis membranes are soaked in ultrapure waterfor 60 minutes to separate strips, then in 20% ethanol for 20 minutes,finally in dialysis buffer for 20 minutes. The dialysis set up isassembled according to the manufacturer's instruction. Each Cell is with150 μL of plasma sample and dialyzed against equal volume of dialysisbuffer (PBS). The assay is performed in duplicate. The dialysis plate issealed and incubated in an incubator at 37° C. with 5% CO₂ at 100 rpmfor 6 hours. At the end of incubation, 50 μL of samples from both bufferand plasma chambers are transferred to wells of a 96-well plate. 50 μLof plasma is added to each buffer samples and an equal volume of PBS issupplemented to the collected plasma sample. 400 μL of precipitationbuffer acetonitrile containing internal standards (IS, 100 nMalprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) isadded to precipitate protein and release compounds. Samples are vortexedfor 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50μL of the supernatant is diluted by 150 μL acetonitrile containinginternal standards:ultra-pure H2O=1:1, and the mixture is used forLC-MS/MS analysis.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein: W is CR^(w) orN; X is CR^(x) or N; Y is CR^(y) or N; Z is —O— or —NR^(z)—; R^(w),R^(x), and R^(y) are each independently hydrogen, halogen, —OR³,—N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN; R^(z) ishydrogen or optionally substituted C₁₋₆ aliphatic; R¹ is —N(R)₂,—N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂; R² is optionally substitutedC₁₋₆ aliphatic; R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;Ring A is optionally substituted 5- to 6-membered monocyclic heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 8- to 10-membered bicyclic heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, optionally substituted 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or optionally substituted 7- to 10-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; L is acovalent bond or a bivalent C₁₋₃ straight or branched hydrocarbon chain;R^(a) is hydrogen, halogen, optionally substituted C₁₋₆ aliphatic,optionally substituted phenyl, optionally substituted 5- to 6-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic carbocyclyl, optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or optionally substituted 7- to10-membered saturated or partially unsaturated bicyclic heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur; each R is independently hydrogen, optionally substituted C₁₋₆aliphatic, optionally substituted 3- to 7-membered saturated orpartially unsaturated carbocyclyl, or optionally substituted 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or two R when attached to the same nitrogen atom are takentogether form an optionally substituted 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 0-2 additionalheteroatoms independently selected from nitrogen, oxygen, and sulfur;and each R′ is independently optionally substituted C₁₋₆ aliphatic oroptionally substituted 3- to 7-membered saturated or partiallyunsaturated carbocyclyl.
 2. The compound of claim 1, wherein Ring A isoptionally substituted 5- to 6-membered monocyclic heteroaryl having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.3-6. (canceled)
 7. The compound of claim 1, wherein R^(a) is halogen,optionally substituted C₁₋₄ alkyl, optionally substituted 5-memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, optionally substituted 3- to 6-memberedsaturated monocyclic carbocyclyl, optionally substituted 3- to6-membered saturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or optionallysubstituted 7-membered saturated, spirocyclic, bicyclic heterocyclylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. 8-11. (canceled)
 12. The compound of claim 7, wherein R^(a) isC₁₋₄ alkyl, 3- to 6-membered saturated monocyclic heterocyclyl having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or 7- to 8-membered saturated, spirocyclic, bicyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.
 13. The compound of claim 1, wherein:

and R^(b) is hydrogen, halogen, —CN, —OR, —SR, —N(R)₂, —NO₂, —C(O)R′,—C(O)OR, —C(O)N(R)₂, —OC(O)R′, —OC(O)N(R)₂, —OC(O)OR, —OSO₂R,—OSO₂N(R)₂, —N(R)C(O)R′, —N(R)SO₂R′, —SO₂R′, —SO₂N(R)₂, —SO₃R′,optionally substituted C₁₋₆ aliphatic, optionally substituted 3- to6-membered saturated or partially unsaturated carbocyclyl, optionallysubstituted 3- to 6-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or optionally substituted 5- to6-membered monocyclic heteroaryl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.
 14. The compound of claim13, wherein

is:


15. The compound of claim 14, wherein

is:


16. The compound of claim 13, wherein R^(b) is hydrogen, halogen,optionally substituted C₁₋₄ alkyl, optionally substituted C₃₋₄cycloalkyl, optionally substituted 3- to 5-membered saturated orpartially unsaturated monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or optionallysubstituted 5-membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur.
 17. Thecompound of claim 16, wherein R^(b) is C₃₋₄ cycloalkyl or C₁₋₄ alkyloptionally substituted with one or more fluoro.
 18. The compound ofclaim 1, wherein L is a covalent bond or —CH₂—.
 19. The compound ofclaim 1, wherein R¹ is —N(H)C(O)R′.
 20. The compound of claim 19,wherein R¹ is —N(H)C(O)(optionally substituted C₁₋₄ alkyl). 21-22.(canceled)
 23. The compound of claim 1, wherein R¹ is —N(H)C(O)N(R)₂.24. The compound of claim 1, wherein R² is C₁₋₄ alkyl. 25-34. (canceled)35. The compound of claim 1, wherein Z is —NR^(z)—.
 36. The compound ofclaim 35, wherein R^(z) is hydrogen.
 37. The compound of claim 1,wherein Z is —O—.
 38. The compound of claim 1, wherein each R isindependently hydrogen or optionally substituted C₁₋₆ aliphatic. 39.(canceled)
 40. The compound of claim 1, wherein: W is CH; R^(x) andR^(y) are each independently hydrogen, optionally substituted C₁₋₆aliphatic, or —CN; and each R is independently hydrogen, optionallysubstituted C₁₋₆ aliphatic, optionally substituted 3- to 7-memberedsaturated or partially unsaturated carbocyclyl, or optionallysubstituted 3- to 7-membered saturated or partially unsaturatedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or two R when attached to the samenitrogen atom are taken together form a 3- to 7-membered saturated orpartially unsaturated monocyclic heterocyclyl having 0-2 additionalheteroatoms independently selected from nitrogen, oxygen, and sulfur.41. The compound of claim 1, wherein the compound is of Formula I-A:

or a pharmaceutically acceptable salt thereof.
 42. The compound of claim13, wherein the compound is of Formula I-B:

or a pharmaceutically acceptable salt thereof.
 43. The compound of claim42, wherein the compound is of Formula I-C:

or a pharmaceutically acceptable salt thereof.
 44. The compound of claim13, wherein the compound is of Formula I-D:

or a pharmaceutically acceptable salt thereof.
 45. The compound of claim44, wherein the compound is of Formula I-E:

or a pharmaceutically acceptable salt thereof.
 46. A compound of FormulaI-1:

or a pharmaceutically acceptable salt thereof, wherein: W is CR^(w) orN; X is CR^(x) or N; Y is CR^(y) or N; Z is —O— or —NR^(z)—; R^(w),R^(x), and R^(y) are each independently hydrogen, halogen, —OR³,—N(R³)₂, —SR³, optionally substituted C₁₋₆ aliphatic, or —CN; R^(z) ishydrogen or optionally substituted C₁₋₆ aliphatic; R¹ is —N(R)₂,—N(R)C(O)R′, —C(O)N(R)₂, or —N(R)C(O)N(R)₂; R² is optionally substitutedC₁₋₆ aliphatic; R³ is hydrogen or optionally substituted C₁₋₆ aliphatic;Ring A is optionally substituted phenyl; L is a covalent bond or abivalent C₁₋₃ straight or branched hydrocarbon chain; R^(a) is hydrogen,halogen, optionally substituted C₁₋₆ aliphatic, optionally substitutedphenyl, optionally substituted 5- to 6-membered monocyclic heteroarylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur, optionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic carbocyclyl, optionally substituted 3- to7-membered saturated or partially unsaturated monocyclic heterocyclylhaving 1-3 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or optionally substituted 7- to 10-membered saturated orpartially unsaturated bicyclic heterocyclyl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; each R isindependently hydrogen, optionally substituted C₁₋₆ aliphatic,optionally substituted 3- to 7-membered saturated or partiallyunsaturated carbocyclyl, or optionally substituted 3- to 7-memberedsaturated or partially unsaturated monocyclic heterocyclyl having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur, ortwo R when attached to the same nitrogen atom are taken together form anoptionally substituted 3- to 7-membered saturated or partiallyunsaturated monocyclic heterocyclyl having 0-2 additional heteroatomsindependently selected from nitrogen, oxygen, and sulfur; and each R′ isindependently optionally substituted C₁₋₆ aliphatic or optionallysubstituted 3- to 7-membered saturated or partially unsaturatedcarbocyclyl, provided that the compound is not:


47. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 48. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 49.A method of inhibiting JAK2 in a subject comprising administering thecompound of claim
 1. 50. A method of treating a disease, disorder, orcondition associated with JAK2, comprising administering to a subject inneed thereof the compound of claim
 1. 51. A method of treating cancer,comprising administering to a subject in need thereof the compound ofclaim
 1. 52-55. (canceled)
 56. The compound of claim 43, wherein: X isCR^(x); Y is N; R^(x) is hydrogen, halogen, —OR³, optionally substitutedC₁₋₆ aliphatic, or —CN; and R′ is independently optionally substitutedC₁₋₂ alkyl or optionally substituted C₃₋₄ cycloalkyl.
 57. The compoundof claim 56, wherein: R^(a) is C₁₋₄ alkyl, 3- to 6-membered saturatedmonocyclic heterocyclyl having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, or 7- to 8-membered saturated,spirocyclic, bicyclic heterocyclyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; and R^(b) is C₃₋₄ cycloalkylor C₁₋₄ alkyl optionally substituted with one or more fluoro.
 58. Thecompound of claim 45, wherein: X is CR^(x); Y is N; R^(x) is hydrogen,halogen, —OR³, optionally substituted C₁₋₆ aliphatic, or —CN; and R′ isindependently optionally substituted C₁₋₂ alkyl or optionallysubstituted C₃₋₄ cycloalkyl.
 59. The compound of claim 58, wherein:R^(a) is C₁₋₄ alkyl, 3- to 6-membered saturated monocyclic heterocyclylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or 7- to 8-membered saturated, spirocyclic, bicyclicheterocyclyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; and R^(b) is C₃₋₄ cycloalkyl or C₁₋₄ alkyloptionally substituted with one or more fluoro.
 60. A pharmaceuticalcomposition comprising a compound of claim 46, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 61.A method of inhibiting JAK2 in a subject comprising administering thecompound of claim
 46. 62. A method of treating a disease, disorder, orcondition associated with JAK2, comprising administering to a subject inneed thereof the compound of claim
 46. 63. A method of treating cancer,comprising administering to a subject in need thereof the compound ofclaim 46.